Compounds and method of treatment having agonist-like activity selective at alpha 2B or 2B / 2C adrenergic receptors

ABSTRACT

Compounds having adrenergic activity which are a selective agonists for one or both of the α 2B  and α 2c  adrenoceptor receptor subtypes in preference to the α 2A  adrenoceptor receptor subtype; the active compound being selected from the group consisting of compounds having the formula  
                 
 
     wherein the dotted lines represent optional bonds provided that two double bonds may not share a common carbon atom; R is H or lower alkyl; X is S or C(H)R 1 , wherein R 1  is H or lower alkyl, but R 1  is absent when the bond between X and the ring represented by  
                 
 
     is a double bond; Y is O, N, S, (CR 1   2 ) y , wherein y is an integer of from 1 to 3, —CH═CH— or —Y 1 CH 2 —, wherein Y 1  is O, N or S; x is an integer of 1 or 2, wherein x is 1 when R 2 , R 3  or R 4  is bound to an unsaturated carbon atom and x is 2 when R 2 , R 3  or R 4  is bonded to a saturated carbon atom; R 2  is H, lower alkyl, halogen, hydroxy, lower alkoxy, lower alkenyl, acyl or lower alkynyl, or, when attached to a saturated carbon atom, R 2  may be oxo; R 3  and R 4  are, each, H, lower alkyl, halogen, lower alkenyl, acyl, lower alkynyl, aryl, heteroaryl, or sub stituted aryl or heteroaryl, wherein said substituent is halogen, lower alkyl, lower alkoxy, lower alkenyl, acyl, lower alkynyl, nitro, cyano, trifluoromethyl, hydroxy, or phenyl or, together, are —(C(R 2 )x)z—; —Y 1 (C(R 2 )x)z′—; —Y 1 (C(R 2 )x)y Y 1 —; —(C(R 2 )x)—Y 1 —(C(R 2 )x)—; —(C(R 2 )x)—Y 1 —(C(R 2 )x)—(C(R 2 )x)— and —Y 1 —(C(R 2 )x)—Y 1 —(C(R 2 )x)— wherein z is an integer of from 3 to 5, z′ is an integer of from 2 to 4 and x and y are as defined above, and further either end of each of these divalent moieties may attach at either R3 or R4 to form a condensed ring structure and the rings formed may be totally unsaturated, partially unsaturated, or totally saturated; and being useful for treating muscle spasticity including hyperactive micturition, diarrhea, diuresis, withdrawal syndromes, pain including neuropathic pain, neurodegenerative diseases, memory and cognition deficits, psychoses including manic disorders and anxiety, hypertension, cardiac ischemia, congestive heart failure, and nasal congestion without sedating or cardiovascular side effects.

FIELD OF THE INVENTION

[0001] The present invention is directed to a method of treatingglaucoma or elevated intraocular pressure and other diseases withsubstantially reduced cardiovascular or sedative side effects byadministering to mammals including humans, compounds which are selectiveagonists of the α2B alone or α2B and α2C adrenergic receptor subtypesand which lack substantial activity at the α2A receptor subtype. Thepresent invention is also directed to novel compounds and pharmaceuticalcompositions adapted for administering said compounds to mammals,including humans.

BRIEF DESCRIPTION OF THE PRIOR ART

[0002] Compounds which have adrenergic activity are well known in theart, and are described in numerous United States and foreign patents andin scientific publications. It is generally known and accepted in theart that adrenergic activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having an adrenergic compound or compounds as the activeingredient are useful for treating glaucoma, chronic pain, nasalcongestion, high blood pressure, congestive heart failure and inducinganesthesia.

[0003] The two main families of adrenergic receptor are termed alphaadrenergic receptors and beta adrenergic receptors in the art, and eachof these two families is known to have subtypes, which are designated byletters of the alphabet, such as α2A, α2B. See the article by Bylund etal, Pharmacol Rev. 46, pp. 121-136(1994).

SUMMARY OF THE INVENTION

[0004] It has been discovered in accordance with the present inventionthat adrenergic compounds which act selectively, and preferably evenspecifically as agonists of the α2B or α2B/α2C (hereinafter referred toas α2B or α2B/2C) receptor subtypes in preference over the α2A receptorsubtype, possess desirable therapeutic properties associated withadrenergics but without having one or more undesirable side effects suchas changes in blood pressure or sedation. For the purposes of thepresent invention, a compound is defined to be a specific or at leastselective agonist of the α2B or α2B/2C receptor subtype(s) if thecompound is at least approximately ten times more potent as an agonistat either the α2B and α2C or both receptor subtypes than at the α2Areceptor subtype, or if the difference in the compound's efficacy at theα2B and α2B/2C receptor relative to the α2A receptor is greater than 0.3and its efficacy at the α2A receptor is ≦0.4.

[0005] Accordingly, the present invention relates to methods of treatinganimals of the mammalian species, including humans, with apharmaceutical composition comprising one or more specific or selectiveα2B or α2B/2C adrenergic agonist compounds as the active ingredient, fortreatment of the many diseases or conditions against which alphaadrenergic compounds are useful, including without limitation glaucoma,reducing elevated intraocular pressure, chronic pain, diarrhea, andnasal congestion. In addition, the compounds of this invention areuseful for treating muscle spasticity including hyperactive micturition,diarrhea, diuresis, withdrawal syndromes, pain including neuropathicpain, neurodegenerative diseases including optic neuropathy, spinalischemia and stroke, memory and cognition deficits, attention deficitdisorder, psychoses including manic disorders, anxiety, depression,hypertension, congestive heart failure, cardiac ischemia and nasalcongestion.

[0006] The present invention is also directed to the pharmaceuticalcompositions used in the above-noted methods of treatment.

[0007] The present invention particularly covers methods for treatingdiseases and conditions where adrenergic compounds are effective fortreatment, but their use is limited because of their generally knownside effects.

DETAILED DESCRIPTION OF THE INVENTION

[0008] Compounds which are used in the pharmaceutical compositions andmethods of treatment of the present invention are selective or specificagonists of the α2B or α2B/2C adrenergic receptor subtypes, inpreference over the α2A receptor subtype. In accordance with the presentinvention, a compound is considered a selective α2B or α2B/2C agonist ifthat compound's difference in efficacy as an agonist of the α2B orα2B/2C receptor subtype(s) compared to the α2A receptor subtype isgreater than 0.3 and its efficacy at the α2A receptor subtype is ≦0.4and/or it is at least approximately 10 times more potent. Preferably,the compounds utilized in accordance with the present invention arespecific agonists of the α2B or α2B/2C receptor subtypes. Specifically,in this regard, a specific agonist is defined in the sense that aspecific α adrenergic agonist does not act as an agonist of the α2Areceptor subtype to any measurable or biologically significant extent.

[0009] A set of agents has been discovered that are functionallyselective for the α2B or α2B/2C—subtypes of said adrenergic receptors.This preferential activity can be determined in a variety of functionalassays such as Cyclic AMP Production, Shimizu et al, J. Neurochem. 16,pp. 1609-1619 (1969); R-SAT (Receptor Selection and AmplificationTechnology), Messier et al, Pharmacol. Toxicol. 76, pp. 308-311(1995)and the Cytosensor microphysiometer, Neve et al, J. Biol. Chem. 267, pp.25748-25753, (1992) using cells that naturally express individualsubtypes or have had one of the subtypes introduced. The cells orrecombinant receptors used should be human or from a species that hasbeen shown to have a similar pharmacology. In the study below, the RSATassay on cells that have been transiently transfected with the human α2A(cdO gene), rat α2B (RNG gene) and human α2C (c4 gene) receptors wasused. The rat α2B receptor has been shown to have a pharmacology that,corresponds to the human α2B receptor (see, for example, Bylund et al.,Pharmocol, Rev. 46, pp. 127-129(1994)).

[0010] In the treatment of glaucoma, particularly, topicaladministration may be used. Any common topical formulation such as asolution, suspension, gel, ointment, or salve and the like may beapplied to the eye in glaucoma and dermally to treat other indications.Preparation of such topical formulations are well described in the artof pharmaceutical formulations as exemplified, for example, byRemington's Pharmaceutical Science, Edition 17, Mack Publishing Company,Easton, Pa.

[0011] If the drug is to be administered systemically, it may beconnected as a powder, pill, tablet or the like or as a syrup or elixirfor oral administration. For intravenous, intra peritoneal, intrathecalor epidural administration, the compound will be prepared as a solutionor suspension capable of being administered by injection. In certaincases, it may be useful to formulate these compounds in suppository oras an extended release formulation, including the dermal patch form, fordeposit on or under the skin or for intramuscular injection.

[0012] Treatment of glaucoma or any other indications known ordiscovered to be susceptible to treatment by adrenergic compounds willbe effected by administration of therapeutically effective dose of oneor more compounds in accordance with the instant invention. Atherapeutic concentration will be that concentration which effectsreduction of the particular condition, or retards its expansion. Incertain instances, the drug potentially could be used in a prophylacticmanner to prevent onset of a particular condition. A given therapeuticconcentration will vary from condition to condition and in certaininstances may vary with the severity of the condition being treated andthe patient's susceptibility to treatment. Accordingly, a giventherapeutic concentration will be best determined at the time and placethrough routine experimentation. However, it is anticipated that in thetreatment of, for example, glaucoma, that a formulation containingbetween 0.001 and 5 percent by weight, preferably about 0.01 to 3% willusually constitute a therapeutically effective concentration. Ifadministered systemically, an amount between 0.001 and 50 mg per kg,preferably between 0.001 and 10 mg per kg body weight per day, but mostpreferably about 0.01 to 1.0 mg/kg, will effect a therapeutic result inmost instances.

[0013] Because the α2B and α2B/2C specific selective agonist compoundslack substantial α2A side effects, treatments of diseases or conditionswith such compounds in accordance with the present invention isadvantageous, particularly when the treatment is directed to a humanhaving cardiovascular problems.

[0014] The general structures of exemplary specific α2B and α2C agonistor selective α2B and α2B/2C agonist adrenergic compounds which are usedin the pharmaceutical compositions and methods of treatment of thepresent invention are provided by general Formulas, below.

[0015] In one aspect of the invention, a compound having selectiveagonist activity at the α2B or α2B/2C adrenergic receptor subtype(s) ascompared to the 2A adrenergic receptor subtype is represented by thegeneral formula

[0016] wherein the dotted lines represent optional bonds provided thattwo double bonds may not share a common carbon atom; R is H or loweralkyl; X is S or C(H)R¹, wherein R¹ is H or lower alkyl, but R¹ isabsent when the bond between X and the ring represented by

[0017] is a double bond; Y is O, N, S, (CR¹ ₂)y, wherein y is an integerof from 1 to 3, —CH═CH— or —Y¹CH₂—, wherein Y¹ is O, N or S; x is aninteger of 1 or 2, wherein x is 1 when R², R³ or R⁴ is bound to anunsaturated carbon atom and x is 2 when R², R³ or R⁴ is bonded to asaturated carbon atom; R² is H, halogen, hydroxy, lower alkyl, alkoxy,alkenyl, acyl, alkynyl, or, when attached to a saturated carbon atom, R₂may be oxo; R₃ and R₄ are, each, H, halogen, lower alkyl, alkenyl, acyl,alkynyl, aryl, e.g. phenyl or naphthyl, heteroaryl, e.g. furyl, thienyl,or pyridyl, and substituted aryl or heteroaryl, wherein said substituentmay be halogen, lower alkyl, alkoxy, alkenyl, acyl, alkynyl, nitro,cyano, trifluoromethyl, hydroxy, etc. or, together, are —(C(R²)x)z—;—Y¹(C(R²)x)z′—; —Y¹(C(R²)x)y Y¹—; —(C(R²)x)—Y¹—(C(R²)x)—;—(C(R²)x)—Y¹—(C(R²)x)—(C(R²)x)— and —Y¹—(C(R²)x)—Y¹—(C(R²)x)— wherein zis an integer of from 3 to 5, z′ is an integer of from 2 to 4 and x andy are as defined above, and further either end of each of these divalentmoieties may attach at either R3 or R4 to form a condensed ringstructure shown generally as

[0018] and the rings formed may be totally unsaturated, partiallyunsaturated, or totally saturated provided that a ring carbon has nomore than 4 valences, nitrogen no more than three and O and S have nomore than two.

[0019] In another aspect of the invention in the above compound isrepresented by the formula

[0020] wherein X may be C(H)R¹ and R¹ is H.

[0021] In said compound of formula II, R₂ may be H and

[0022] may represent a furanyl radical.

[0023] In such furanyl derivatives of Formula II, R³ and R⁴ together maybe (CH)₄, or R³ may be Hand R⁴ may be t-butyl, or R³ and R⁴ may be H, orR³ may be H and R⁴ may be methyl or ethyl.

[0024] Alternatively, in the compound of Formula I, R¹ may be methyl and

[0025] may represent a furanyl radical.

[0026] Alternatively, in said compounds of Formula II, R² may be H and

[0027] may represent a thienyl radical.

[0028] In such thienyl derivatives of Formula II, R³ and R⁴, together,may represent (CH₂)₄, or R³ may be phenyl and R⁴ may be H, or R³ and R⁴,together, may represent (CH₂)₃S, or R³ and R⁴ may be H, or R³ and R⁴,together, may represent (CH)₄, or may be R³ may be H and R⁴ may bemethyl, or R³ may be bromo and R⁴ may be H, or R³ may be hydrogen and R⁴may be chloro, or R³ may be methyl and R⁴ may be hydrogen.

[0029] Alternatively, in the compounds of Formula II

[0030] may represent a cyclohexyl radical.

[0031] In such cyclohexyl derivatives of Formula II, R² may be hydrogenand R³ and R⁴ may, together, represent (CH)₄, or R² may be oxo and R³and R⁴, together, may be (CH)₄, or R² may be hydrogen or oxo and R³ andR⁴, together, may represent (CH)₂S, or R² may be hydrogen and R³ and R⁴may, together, represent (CH₂)₄, forming an octahydronaphthalene, or R²may be oxo and R³ and R⁴ may, together, represent (CH₂)₄, or R² may beoxo and R³ and R⁴, together, may represent (CH)₂C(CH₃)(CH), or R² may behydrogen and R³ and R⁴, together, may represent S(CH₂)₂, or R², R³ andR⁴ may be H, or R² may be oxo and R³ and R⁴, together, may represent(CH)₂ C(OCH₃)CH, or R³ and R⁴ together may represent—Y¹—C(R₂)_(x)—C(R₂)_(x)—Y¹— wherein Y¹ is N, forming atetrahydroquinoxaline wherein R² may be hydrogen or oxo.

[0032] Alternatively, in the compounds of Formula II

[0033] may represent a tetrahydroquinoxaline radical wherein R³ and R⁴together are —Y¹—C(R₂)_(x)—C(R₂)_(x)—C(R₂)_(x)— wherein Y¹ is N. In suchtetrahydroquinoline derivatives (R²)_(x) may be hydrogen or oxo; or mayrepresent a tetrahydroisoquinoline radical wherein R³ and R⁴ togetherare —C(R₂)_(x)—Y¹—C(R₂)_(x)—C(R₂)_(x)— wherein Y¹ is N and (R²)_(x) maybe hydrogen or oxo.

[0034] Alternatively, in the compounds of Formula II

[0035] may represent a cyclopentyl radical.

[0036] In such cyclopentyl derivatives of Formula II, R² may be H and R³and R⁴, together, may represent (CH)₄, or R² may be oxo and R³ and R⁴,together, may represent (CH)₄, or R² may be hydrogen and R³ and R₄,together, may represent (CH₂)₃.

[0037] In another aspect of the invention, Y is (CH₂)₃ and X may be CHand R² may be oxo or X may be CH₂ and R² may be H and R³ and R⁴,together, may represent (CH)₄. Alternatively, R³ and R⁴, together, mayrepresent (CH)₄, Y may be CH₂C(CR¹ ₂)₂ wherein R¹ is hydrogen, or Y maybe —CH2C(Me)— and R² may be hydrogen or oxo.

[0038] Finally, in the compounds of Formula II

[0039] may represent a phenyl radical.

[0040] In such phenyl derivatives of Formula I, X may be CH₂, R maybe Hor CH₃, R², R³ and R⁴ may be H, or R³ and R⁴, together, representO(CR²)₂O to provide a 1,4-benzodioxan derivative, or alternatively, Xmay be S and R², R³ and R⁴ may be H.

[0041] In another aspect of the invention, said compound has the formula

[0042] wherein Y is S or O.

[0043] In such compound of Formula III, X may be C(H)R¹, R, R¹, R², R³and R⁴ may be H and Y may be O or S.

[0044] In another aspect of the invention, said compound has the formula

[0045] and R³ and R⁴, together, represent (CH)₄.

[0046] In such compounds of Formula IV, Y¹ may be O, R² may be oxo and Xis CH or CH₂, or one of R² is hydroxy and the other may be H, or R² maybe H.

[0047] In such compounds of Formula IV, Y¹ may be S, X may be CH₂ and R²may be oxo, or R² may be H and X may be CH and R² may be oxo.

[0048] In another aspect of the invention, the compound having selectiveactivity at the 2B or 2B and 2C adrenergic receptor subtype(s) ascompared to the 2A adrenergic receptor subtype is represented by theformula

[0049] alternatively W is a bicyclic radical selected from the groupconsisting of

[0050] wherein R⁵, R⁶, R⁷ and R⁸ are selected from the group consistingof H and lower alkyl provided that at least one of R⁵ and R⁶ or R⁶ andR⁷ are OC(R⁹)C(R⁹)N(R) to form a condensed ring with

[0051] wherein R⁹ is H, lower alkyl or oxo; and

[0052] wherein R¹⁰ is H, lower alkyl, phenyl or lower alkyl substitutedphenyl, and Z is O or NH. Compounds wherein W is norbomyl are disclosedand claimed in commonly assigned co-pending application 09/003902, filedon Jan. 7, 1998, which is hereby incorporated by reference in itsentirety.

[0053] In one aspect of the invention Z may be O and W may be

[0054] and R¹⁰ may be selected from the group consisting of H, phenyland o-methylphenyl, e.g. R¹⁰ may be o-methylphenyl.

[0055] In another aspect of the invention W may be

[0056] wherein Z may be NR, R may be methyl or hydrogen, one of (R⁹)_(x) may be H and R⁵ may be H.

[0057] Alternatively, W may be

[0058] wherein R may be H and R⁸ may be methyl.

[0059] It is understood that wherein a reference to lower alkyl, alkoxy,alkenyl or alkynyl is made above, it is intended to mean radicals havingfrom one to eight carbons, preferably from one to four carbon atoms.Where reference to aryl is made above, it is intended to mean radicalsof from six to fourteen carbon atoms, preferably from six to ten carbonatoms. Where reference is made to halogen, fluoro and chloro arepreferred.

[0060] The invention is further illustrated by the following examples(including general synthetic schemes therefore) which are illustrativeof

[0061] various aspects of the invention and are not intended as limitingthe scope of the invention as defined by the appended claims.

EXAMPLE A

[0062] Synthesis of1-dimethylsulfamoyl-2-t-butyldimethylsilyl-5-imidazolecarboxaldehyde:

[0063] Procedure-

[0064] Imidazole (1) (20.0 g, 0.29 mol), triethylamine (41.OmL, 0.29mol) and N,N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were addedto 320 mL of benzene. The reaction was stirred for 48 h at roomtemperature (rt) and then filtered. The filtrate was collected andconcentrated under reduced pressure. Vacuum distillation of the crudeproduct (0.5 mmHg, 115°-118° C.) afforded 38.7 g (76%) of a clear andcolorless oil. Upon cooling the product solidifies to give whitecrystals (2). 1-(Dimethylsulfamoyl) imidazole (2) (18.8 g, 0.11 mol) wasadded to 430 mL of tetrahydrofuran (THF). The solution was cooled to−78° C. A solution of n-butyl lithium (n-BuLi) in hexane (1.6M, 70.9 mL,0.11 mol) was added dropwise to the reaction flask. Upon completion, thereaction was stirred for 1 h at −78° C. t-Butyldimethylsilylchloride(17.8 g, 0.12 mol) in 50 mL of THF was added via cannula to thereaction. After the addition was completed the reaction mixture waswarmed slowly to rt and then stirred for 24 h. The reaction was dilutedwith water and the organic layer separated. The organic phase was washedwith brine and then dried over sodium sulfate. The mixture was filteredand the filtrate concentrated under reduced pressure. Columnchromatography (20% ethyl acetate/hexane as eluant) afforded a lightyellow solid. Recrystallization from pentane gave 30 g (94%) of whitecrystals (3).

[0065] 1-Dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (3) (5.0 g,17.3 mmol) was added to 100 mL of THF. The solution was cooled to −20°C. A solution of secondary butyl lithium (s-BuLi) in hexane (1.3M, 14.6mL, 19 mmol) was added dropwise to the reaction flask. Upon completionthe reaction was stirred for 1 h at −20° C. 8 mL of dimethylformamide(DMF) was added to the reaction and then stirred at rt for 3.5 h. Thereaction was diluted with water and the organic layer separated. Theorganic phase was washed with brine and then dried over sodium sulfate.The mixture was filtered and the filtrate concentrated under reducedpressure. Column chromatography (20% ethyl acetate/hexane) afforded alight yellow oil. Upon cooling the product solidifies to give yellowcrystals of1-dimethylsulfamoyl-2-t-butyldimethylsilyl-5-imidazolecarboxaldehyde(4).

EXAMPLE B-1

[0066] Procedure for Preparation of4(5)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylnethyl)-1H-imidazole,hydrogen chloride salt:

[0067] Procedure-

[0068] 7-Methoxy-1-tetralone (1) (15 g, 8.5 mmol) and1-dimethylsulfamoyl-2-t-butyldimethylsilyl-5-imidazolecarboxaldehyde (2)(2.7 g, 8.5 mmol) were added to 8.5 mL of a 40% solution of sulfuricacid. The reaction was heated for 24 h at 90° C. After cooling to rt,the reaction was made basic with excess concentrated ammonium hydroxide.The mixture was extracted twice with THF. The organic layers werecombined and washed with brine. The organic layer was separated anddried over sodium sulfate. The mixture was filtered and the filtrateconcentrated under reduced pressure to afford 2.7 g of a yellow solid(3) comprising 3-(3H-imidazole-4(5)ylmethylene)-7-methoxy chroman-4-one.The crude product was suspended in 100 mL of ethanol and a palladium oncarbon catalyst (10%, 0.27 g) added. The mixture was shaken in a Parrhydrogenator apparatus while under 40 psi of hydrogen. After 19 h thereaction mixture was filtered through Celite and the filtrateconcentrated under reduced pressure. Column chromatography with 7%methanol in chloroform afforded 1.⁰⁵ g (46%) of a tan color solidcomprising2-[3H-Imidazole-4(5)-ylmethyl]-7-methoxy-3,4-dihydro-2H-naphthalen-1-one(4)(B-1a). (4) (0.5 g, 1.95 mmol) was added to 20 mL of methanol. Sodiumborohydride (74 mg, 1.95 mmol) was added to the solution. After stungfor 2.5 h at rt the reaction mixture was quenched with water. Thereaction mixture was then extracted twice with ethyl acetate. Theorganic layers were combined and washed with brine. The organic layerwas separated and dried over sodium sulfate. The .mixture was filteredand the filtrate concentrated under reduced pressure to afford 0.5 g ofa white solid (5) comprising2-[3H-Imidazole4(5)-ylmethyl]-7-methoxy-3,4-dihydro-2H-naphthalen-1-ol.The crude product was dissolved in 26 mL of dichloromethane.Triethylsilane (2.5 mL, 15.6 mmol) and trifluoroacetic acid (4.8 mL,62.3 mmol) were added and the reaction stirred at rt for 22 h. Thereaction was made basic with 2N NaOH and the organic layer separated andwashed with brine. The solution was dried over sodium sulfate. Themixture was filtered and the filtrate concentrated under reducedpressure. Column chromatography with 7% methanol in chloroform afforded0.39 g (83%) of a tan color oil (6). The product was dissolved inmethanol and an excess of hydrogen chloride (HCl) in ether was added.The solution was concentrated under reduced pressure to yield 0.3 g of atan color solid. Column chromatography with 7% methanol in chloroformafforded 0.25 g (46%) of4(5)-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole,hydrogen chloride salt (B-1) as white crystals (7) afterrecrystallization from a mixture of acetone and methanol.

[0069]¹H NMR (300 MHz, CD₃OD) 8.83 (s, 1H), 7.38 (s, 1H), 6.95 (d, 1H,J=8.5 Hz), 6.66 (d, 1H, J=8.4 Hz), 6.57 (s, 1H), 3.73 (s, 3H), 2.71-2.81(m, 5H), 2.43-2.52 (m, 1H), 1.90-2.14 (m, 2H), 1.40-1.51 (m, 1H).

[0070] Following the procedure of Example B-1 various fused ringcompounds are reacted to yield the imidazole derivatives listed below.Example B-2(a-d) 4-chromanone (2a)3-(3H-imidazol-4(5)-ylmethylene)chroman-4-one (2b)3-(3H-imidazol-4(5)-ylmethyl)chroman-4-one (2c)3-(3H-imidazol-4(5)-ylmethyl)chroman-4-ol (2d)4(5)-chroman-3-ylmethyl-1H-imidazole Example B-3(a-b) 1-tetralone (3a)2-(3H-imidazol-4(5)-ylmethyl)-3,4-dihydro-2H-naphthalen-1-one (3b)4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole ExampleB-4(a-b) 4-methyl-1-tetralone (4a)4(5)-(4-methyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole(4b)2-(3H-imidazol-4(5)-ylmethyl)-4-methyl-3,4-dihydro-2H-naphthalen-1-oneExample B-5(a-b) Thiochroman (5a)3-(3H-imidazol-4(5)-ylmethylene)thiochroman-4-one (5b)3-(3H-imidazol-4(5)-ylmethyl)thiochroman-4-one Example B-6 The hydrogenchloride salt of the previous compound is prepared by step 5 of themethod of Example B-1, above. Thiochroman4(5)-thiochroman-3-ylmethyl-1H-imidazole Example B-7(a-c) 1-indanone(7a) 2-(3H-imidazol-4(5)-ylmethylene)indan-1-one (7b)2-(3H-imidazole-4(5)-ylmethyl)indan-1-one (7c)4(5)-indan-2-ylmethyl-1H-imidazole Example B-8(a-b) 7-methyl-1-tetralone(8a)2-(3H-imidazol-4(5)-ylmethyl)-7-methyl-3,4-dihydro-2H-naphthalen-1-one(8b)4(5)-(7-methyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole Thehydrogen chloride salt of this compound is prepared by the method ofExample B-6. Example B-9(a-c) 4-keto-4,5,6,7-tetra- (9a)4(5)-(4,5,6,7-tetrahydrobenzo[b]thiophen-5-ylmethyl)-1H-imidazolehydrothianaphthene The hydrogen chloride salt of this compound isprepared by the method of Example B-6. (9b)5-(3H-imidazol-4(5)-ylmethyl)-6,7-dihydro-5H-benzo[b]thiophen-4-one Thehydrogen chloride salt of this compound is prepared by the method ofExample B-6. (9c) 5-(octahydrobenzo[b]thiophen-5-ylmethyl)-1H-imidazoleExample B-10 4,4-Dimethyl-1-tetralone4(5)-(4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazoleExample B-11(a-b) 1-Benzosuberone (11a)4(5)-(6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylmethyl)-1H-imidazole(11b)6-(1H-imidazol-4(5)-ylmethylene)-6,7,8,9-tetrahydrobenzocyclohepten-5-one

EXAMPLE C-1

[0071] Procedure for Preparation of4(5)-thiophen-3-ylmethyl-1H-imidazole:

[0072] Procedure-

[0073] 1-(Dimethylsulfamoyl)imidazole (1) (2.0 g, 11.4 mmol) is taken upin 42 mL of anhydrous THF and cooled to −78° C. n-BuLi (6.6 mL, 10.6mmol) is added dropwise to the solution of (1). The resultant solutionis stirred at —78° C. for 30 min. Tert-butyldimethylsilylchloride(TBSCl) (1.6 g, 10.6 mmol) in 8 mL of THF is added to the reaction. Thereaction is warmed to rt and stirred overnight. The next day thereaction is cooled to −20° C. and 7.3 mL (11.6 mmol) of n-BuLi added.After stirring at −20° C. for 45 min, 3-thiophene carboxaldehyde (2)(1.0 mL, 11.6 mmol) is added to the reaction mixture. Then reaction iswarmed to rt and stirred overnight. The next day the reaction isquenched with water and diluted with ethyl acetate. The organic layer iswashed with water followed by brine. The organic phase is dried oversodium sulfate and the solvent removed under reduced pressure. Flashchromatography (2:5 ethyl acetate/hexane) affords 3.0 g (7.5 mmol) of2-(t-butyldimethylsilyl)-5-(hydroxythiophen-2-ylmethyl)imidazole-1-sulfonicacid dimethylamide (3). (3) (1.5 g, 3.74 mmol) is taken up in 37 mL ofTHF. A 1M solution of tetra-n-butylammonium fluoride (TBAF) in THF (4.1mL, 4.1 mmol) is added dropwise to the solution of (3). The reaction isstirred overnight at rt. The next day the reaction is quenched withwater and then extracted with ethyl acetate. The organic layer is washedwith water followed by brine. The organic phase is dried over sodiumsulfate and the solvent removed under reduced pressure. 0.94 g (3.3mmol) of 5-(hydroxythiophen-2-ylmethyl)imidazole-1-sulfonic aciddimethylamide (4) is recovered. (4) (0.5 g, 1.74 mmol) is taken up in 23mL of dichloromethane, to the solution is added 2.2 mL (13.9 mmol) oftriethylsilane and 4.3 mL (55.7 mmol) of trifluoroacetic acid. Thereaction is stirred at rt overnight and then quenched with water andneutralized with solid sodium bicarbonate. The organic layer is washedwith water followed by brine. The organic phase is dried over sodiumsulfate and the solvent removed under reduced pressure. Flashchromatography using a 1:1 mixture of ethyl acetate and hexane affords0.42 g (1.55 mmol) of 5-(thiophen-2-ylmethyl)imidazole-1-sulfonic aciddimethylamide (5). (5) (0.42 g, 1.55 mmol) is taken up in 10 mL of a1.5N HCl solution and heated at reflux for 3 h and then stirred at rtovernight. The reaction is diluted with ethyl acetate, neutralized withsolid sodium bicarbonate and then made basic with 2N NaOH. The organiclayer is washed with water followed by brine. The organic phase is driedover sodium sulfate and the solvent removed under reduced pressure.Flash chromatography using a 10:1 mixture of chloroform and methanolaffords 0.17 g (1.0 mmol) of 4(5)-thiophen-3-ylmethyl-1H-imidazole (6)(C-1).

[0074]¹H NMR (300 MHz, CD₃OD) 7.52 (s, 1H), 7.25-7.27 (m, 1H), 6.96-7.01(m, 2H), 6.77 (s, 1H), 3.98 (s, 2H).

EXAMPLE C-2

[0075] The 2-carboxaldehyde isomer of 3-thiophene carboxaldehyde issubstituted into the method of Example C-1 to yield4(5)-thiophen-2-ylmethyl-1H-imidazole

EXAMPLE C-3

[0076] 5-Methyl-2-thiophene carboxaldehyde of 3-thiophene carboxaldehydeis substituted into the method of Example C-1 to yield4(5)-(5-methylthiophen-2-ylmethyl)-1H-imidazole

EXAMPLE C-4

[0077] 5-Chloro-2-thiophene carboxaldehyde of 3-thiophene carboxaldehydeis substituted into the method of Example C-1 to yield4(5)-(5-chlorothiophen-2-ylmethyl)-1H-imidazole

EXAMPLE C-5

[0078] 2-Furan carboxaldehyde is substituted into the method of ExampleC-1 to yield 4 (5)-furan-2-ylmethyl-1H-imidazole

EXAMPLE C-6

[0079] 3-Furan carboxaldehyde is substituted into the method of ExampleC-1 to yield 4(5)-furan-3-ylmethyl-1H-imidazole

EXAMPLE C-7

[0080] 5-Methyl-2-furan carboxaldehyde is substituted into the method ofExample C-1 to yield 4(5)-(5-methylfuran-2-ylmethyl)-1H-indazole

EXAMPLE C-8

[0081] Benzaldehyde is substituted into the method of Example C-1 toyield 4(5)-benzyl-1H-imidazole

EXAMPLE C-9

[0082] 2-Thianaphthene carboxaldehyde is substituted into the method ofExample C-1 to yield 4(5)-benzo[b]thiophen-2-ylmethyl-1H-imidazole

EXAMPLE C-10

[0083] 2-Benzofuran carboxaldehyde is substituted into the method ofExample C-1 to yield 4(5)-benzofuran-2-ylmethyl-1H-imidazole

EXAMPLE C-11

[0084] 5-Ethyl-2-furan carboxaldehyde is substituted into the method ofExample C-1 to yield 4(5)-(5-ethylfuran-2-ylmethyl-1H-imidazole

EXAMPLE C-12

[0085] 4-Bromo-2-thiophene carboxaldehyde is substituted into the methodof Example C-1 to yield 4(5)-(4-bromothiophen-2-ylmethyl)-1H-imndazole

EXAMPLE C-13

[0086] 4-Phenyl-2-thiophene carboxaldehyde is substituted into themethod of Example C-1 to yield4(5)-(4-phenylthiophen-2-ylmethyl)-1H-imidazole

EXAMPLE C-14

[0087] 4-Methyl-2-thiophene carboxaldehyde is substituted into themethod of Example C-1 to yield4(5)-(4-methylthiophen-2-ylmethyl)-1H-imidazole, hydrochloride salt

EXAMPLE D-1

[0088] Procedure for Preparation of oxazolidin-2-ylidene-(3-phenylbicyclo[2.2.1]hept-2-yl) amine:

[0089] Procedure-

[0090] The endo exo relative stereochemistry of the compound wasprepared, by making the P-nitrostyrene as shown above. Treatment of amethaol solution of benzaldehyde (10 g, 94.3 mmole) with nitromethane(51 ml, 943 mmol) in the presence of sodium hydroxide (3N in methanol topH=8) afforded the nitro alcohol in 60% yield. Dehydration of thealcohol was effected by treatment with methanesulfonyl chloride (3.56 g,31.1 mmole) followed by triethylamne (6.3 g, 62.2 mmol) indichloromethane (35 ml) to give 97% yield of product. Kugelrohrdistillation was done to purify compound. Construction of thebicyclo[2.2.1]heptane skeleton was carried out in one step. TheDiels-Alder reaction was conducted by warming the nitrostyrene (4.5 g,30.2 mmole) with cyclopentadiene (3.98 g, 60.4 mmole) in 1,2-dichloroethane (10ml). The Diels-Alder reaction proceeds inapproximately a 3:1 endo:exo nitro ratio. Both the ratio and relativestereochemistry was demonstrated through x-ray analysis. Reduction ofboth the nitro group and the olefin was carried out under an atmosphereof hydrogen in the presence of 10% by weight palladium on charcoal.Separation of isomers was conveniently carried out at this stage usingflash chromatography with 5% ammonia-saturated methanol indichloromethane. The amine (0.7 g, 3.74 mmole) was treated first withchoroethylisocyanate (0.38ml, 4.49 mmole) to afford the chloroethylurea,which was then warmed in the presence of aqueous NaHCO₃ solution toafford oxazolidin-2-ylidene-(3-phenyl bicyclo[2.2.1]hept-2-yl) amine(D-1) in 51% yield.

[0091]¹H NMR (300 MHz, CDCl₃) d 1.36-1.80 (m, 6H), 2.14 (d, 1H, J=4.40Hz), 2.37 (s, 1H), 2.65 (s, 1H), 3.71-3.78 (m, 2H), 3.95-3.98 (m, 1H),4.19-4.25 (t, 2H, J=17.15 Hz, 3=8.36 Hz), 7.17-7.29 (m, 5H).

EXAMPLE D-2

[0092] Oxazolidin-2-ylidene-(3-o-tolyl bicyclo[2.2.1]hept-2-yl)amine isprepared by substituting o-methyl P-nitrostyrene in the method of D-1

EXAMPLE D-3

[0093] Bicyclo[2.2.l]hept-2-yl oxazolidin-2-ylidene amine is prepared bysubstituting nitroethene in the method of D-1

EXAMPLE E-1

[0094] Procedure for Preparation ofimidazolidin-2-ylidene-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)amine:

[0095] Procedure-

[0096] To 2-amino4-nitrophenol (1) (4.00 g, 25.95 mmol), triethylamine(15.20 mL, 109.0 mmol) and 4-dimethylarninopyridine (0.063 g, 0.52 mmol)slurried in anhydrous CH₂Cl₂ (250 mL) at 0° C. under argon addedchloroacetyl chloride (2.27 mL, 28.55 mmol) via syringe. After refluxingfor 72 h pure product was filtered off and washed with water. The motherliquor was washed successively with phosphoric acid (0.5M), saturatedsodium bicarbonate, water and brine and then dried over MgSO₄. Thissolution was adhered to silica and purified by flash chromatography onsilica with hexane/ethyl acetate (4:6) to give additional product Thecombined solids were dried in vacuo to give pure6-nitro-4H-benzo[1,4]oxazin-3-one (2) (4.12 g) in 82% yield. To a slurryof (2) (1.49 g, 7.65 mmol) in anhydrous THF (4OmL) under argon in a2-neck round-bottom flask equipped with a reflux condenser was addedborane-dimethyl sulfide complex (15.3 mL, 30.62 mmol). The mixture washeated at reflux until starting material was no longer observed via thinlayer chromatography (2 h). The reaction mixture was cooled to rt andcarefully quenched by the dropwise addition of methanol. The resultingmixture was then refluxed an additional 10 minutes. The crude reactionmixture was concentrated in vacuo and purified by flash chromatographyon silica with hexane/ethyl acetate (8:2) to give pure6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (3) (1.36 g) as an orange solidin 99% yield. To (3) (0.032 g, 0.178 mmol) and formalin (37% in H₂O,0.20 mL, 2.67 mmol) in anhydrous acetonitrile (1.5 mL) at ambienttemperature was added sodium cyanoborohydride (0.034 g, 0.534 mmol).This solution was stirred for 30 min before adding glacial acetic acid(0.032 mL, 0.534 mmol). The resulting mixture was stirred an additional16 h. The organics were taken up in diethyl ether and washedsuccessively with NaOH (2N) and brine, dried over MgSO₄ and concentratedin vacuo. The resulting solids were purified by flash chromatography onsilica with hexane/ethyl acetate (7:3) to give pure4-methyl-6-nitro-3,4-dihydro-2H-benzo[l,4]oxazine (4) (0.031 g) in 93%yield. To (4) (2.16 g, 11.12 mmol) and 10% palladium on carbon (0.216 g,10 wt. %) under argon was added methanol (MeOH) (30 mL) followed by THF(30 mL). Hydrogen was bubbled thru the resulting slurry until no (4)remained visible by thin layer chromatography (2 h). Celite was addedand the mixture was filtered through a bed of celite followed by a MeOHwash. The resulting solution was concentrated in vacuo to give pure4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylanine (5) (1.86 g) as apale purple oil in 100% yield which was carried on without furtherpurification. To (5) (1.86 g, 11.34 mmol) and imidazoline-2-sulfonicacid (1.84 g, 12.24 mmol) in anhydrous acetonitrile (50 mL) under argonat 0° C. was added triethylarnine (3.26 mL, 23.36 mmol). This solutionwas gradually warmed to ambient temperature and stirred for 16 h. Atthat time an additional amount of imidazoline-2-sulfonic acid (0.86 g,5.55 mmol) was added and the resulting mixture was stirred an additional5 h. This solution was concentrated in vacuo and the residues were takenup in H₂O. The organics were extracted into CH₂Cl₂ and washed twice withNaOH and then brine, dried over Mg₄ and concentrated in vacuo. Theresulting foam was purified by flash chromatography on silica with 20%methanol (saturated with ammonia) in chloroform to give pureindazolidin-2-ylidene-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)amine(6) (E-1) (0.905 g) in 34% yield.

[0097]¹H NMR (CDCl₃): 2.81 (s, 3H); 3.26 (t, J=8.9 Hz, 2H); 3.60 (s,41); 4.26 (m, 21); 4.60 (vbrs, 2H); 6.34 (dd, J=8.2 Hz, J=2.4 Hz, 1H);6.39 (d, J=2.4 Hz, 1H); 6.68 (d, J=8.2 Hz, 1H).

EXAMPLE F & G

[0098] Procedure for Preparation of 6-(imidazolidin-2-ylideneamino)-5-methyl-4H-benzo[1,4]oxazin-3-one (F) andImidazolidin-2-ylidene-(5-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)amine(G):

[0099] Procedure-

[0100] To 2-amino-3-methylphenol (1) (14.72 g, 0.120 mol), triethylamine(35.0 mL, 0.251 mol) and 4-dimethylaminopyridine (0.29 g, 2.39 mmol) inanhydrous CH₂Cl₂ (100 mL) at 0° C. under argon was added chloroacetylchloride (10.0 mL, 0.126 mol) dropwise via syringe. After the additionwas complete the resulting solution was refluxed for 24 h. The organicswere washed successively with phosphoric acid (0.5M), saturated sodiumbicarbonate, water and brine and then dried over MgSO₄. The resultingsolution was concentrated and taken up in THF to which ether was added.The resulting crystals were filtered off to give pure5-methyl-4H-benzo[1,4]oxazin-3-one (2) (12.30 g) in 63% yield. To (2)(14.64 g, 89.72 mmol) dissolved in concentrated H₂SO₄ (65 mL) at −10° C.was added 70% concentrated HNO₃ (8.08 g, 89.72 mmol) in concentratedH₂SO₄ (25 mL) with rapid mechanical stirring at a rate whereby theinternal temperature was maintained below −5° C. As soon as the additionwas complete the mixture was poured onto crushed ice (500 mL) and theresultant solids were filtered off and slurried in cold water (300 mL)while sufficient NaOH was added to adjust the pH to 7. The recoveredyellow powder was dissolved in THF, adhered to silica and purified byflash chromatography with 60% hexane and ethyl acetate to give thenitrated product as a mixture of two regioisomers, i.e. the desired6-substituted aromatic comprising6-nitro-5-methyl-4H-benzo[l,4]oxazin-3-one (3) (55%) and the8-substituted by-product comprising8-nitro-5-methyl-4H-benzo[1,4]oxazin-3(4) (22%). These isomers areseparated with difficulty at this point and were carried on to the nextstep as a mixture. To a mixture of (3) (1.93 g, 9.27 mmol) and (4) (0.48g, 2.32 mmol) dissolved in a solution of MeOH (300 mL) and THF (300 mL)under argon was added 10% palladium on carbon (1.20 g). The resultingsolution was subjected to H₂ at one atmosphere pressure. After 16 h thecatalyst was filtered off and the resulting solution was concentrated invacuo and purified by flash chromatography on silica with 50% hexane andethyl acetate to give 6-anino-5-methyl4H-benzo[1,4]oxazin-3-one (5)(0.96 g) in 46% yield and 8-amino-5-methyl-4H-benzo[1,4]oxazin-3-one (6)(0.17 g) in 8% yield. (5) (1.20 g, 6.74 mmol), imidazoline-2-sulfonicacid (2.02 g, 13.48 mmol) and triethylamine (2.35 mL, 16.85 mmol) wereheated at reflux in anhydrous acetonitrile (50 mL) under argon for 48 h.At that time an additional amount of imidazoline-2-sulfonic acid (1.0 g,6.74 nmuol) and triethylamine (1.41 mL, 10.12 mmol) were added and theresulting mixture was stirred an additional 24 h. This solution wasconcentrated in vacuo and the residues were taken up in a solution ofCHCl₃/isopropyl alcohol (3:1) and washed successively with NaOH (1N) andbrine, dried over MgSO₄ and concentrated in vacuo. The resulting foamwas purified by flash chromatography on silica with 20% methanolsaturated with ammonia in chloroform to give6-(imidazolidin-2-ylideneamino)-5-methyl4H-benzo[1,4]oxazin-3ne (7)(0.42 g) as a foam in 27% yield along with 55% recovered startingmaterial. The HCl salt was recrystallized from a mixture of ethanol anddiethyl ether (EtOH/Et₂O) to give fine white needles.

[0101]¹H NMR (DMSO): 2.10 (s, 3H); 3.59 (s, 4H); 4.53 (s, 2H); 6.83 (d,J=8.6 Hz, 1H); 6.90 (d, J=8.6 Hz, 1H); 8.07 (brs, 2); 10.15 (vbrs, 1H);10.42 (s, 1H).

[0102] (6) (0.222 g, 1.35 mmol), imidazoline-2-sulfonic acid (0.223 g,1.49 mmol) and triethylamine (0.415 mL, 2.98 mmol) were heated at 95° C.in anhydrous acetonitrile (10 mL) in a sealed tube for 2 h. At that timean additional amount of imidazoline-2-sulfonic acid (0.112 g, 0.75 mmol)was added and the reaction was continued for an additional 16 h. Thissolution was concentrated in vacuo and the residues were taken up in asolution of CHCl₃/isopropyl alcohol (3:1) and washed successively withNaOH (2N) and brine, dried (MgSO₄) and concentrated in vacuo. Theresulting oil was recrystallized from CHCl₃ to give pure6-(indazolidin-2-ylideneamino)-5-methyl4H-benzo[1,4]oxazin-3-one (8) (F)(0.048 g) as a white powder in 15% yield along with 35% recoveredstarting material. To a slurry of (8), (0.08 g, 0.321 mmol) in anhydrousTHF (50 mL) under argon in a 3-neck round-bottom flask equipped withreflux condenser was added borane-dimethyl sulfide complex (0.48 mL,0.936 mmol). The mixture was heated at reflux until starting materialwas no longer observed via thin layer chromatography (3 h). The reactionmixture was cooled to room temperature and carefully quenched by thedropwise addition of methanol. The crude reaction mixture wasconcentrated in vacuo and purified by flash chromatography on silicausing 20% methanol saturated with ammonia/chloroform to giveindazolidin-2-ylidene-(5-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)amine(9) (G) (0.03 g) as the HCl salt in 37% yield.

[0103]¹H NMR (CDCl₃): 2.07 (s, 3H); 3.46 (t, J=4.3 Hz, 2H); 3.55 (s,4H); 4.24 (t, J=4.3 Hz, 2H); 5.60 to 5.95 (vbrs, 2H); 6.44 (d, J=8.0 Hz,1H); 6.57 (d, J=8.0 Hz, 1H).

EXAMPLE H

[0104] Procedure for Preparation of 4(5)-phenylsulfanyl-1H-imidazole:

[0105] Procedure-

[0106] 1-(N,N-dimethylsulfamoyl)imidazole (1.5 g, 8.6 mmol) was taken upin 28 mL of THF. The solution was cooled to −78° C. and n-BuLi (5.4 mL,8.6 mmol) added dropwise via syringe. After stirring at −78° C. for 1 hTBSCl (1.3 g, 8.56 mmol) in 10 mL of THF was added. The bath was removedand the reaction allowed to warm-up to rt. The reaction mixture wasstirred overnight. The reaction mixture was cooled to −20° C. and n-BuLi(5.4 mL, 8.6 mmol) added. After 45 min phenyldisulfide (1.9 g, 8.6 mmol)in 8 mL of THF was added. The reaction mixture was stirred at rt for 48h. The reaction mixture was quenched with saturated ammonium chlorideand extracted with ethyl acetate. The organic layer was collected andwashed with water and then brine. The solution was dried over sodiumsulfate and the solvent removed under reduced pressure. Flashchromatography (2.5% EtOAc/hexane) afforded 2.8 g (7.0 mmol) of2-(t-butyldimethylsilyl)-5-phenylsulfanylimidazole-1-sulfonic aciddimethylamide (1) as a yellow color oil. The compound (1) (2.8 g, 7.0mmol) was dissolved in THF and the solution cooled to 0° C. TBAF (7.0mL, 7.0 mmol) was added dropwise to the solution. The reaction mixturewas stirred overnight at rt. The next day the reaction was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith water followed by brine. The solution was dried over sodium sulfateand the solvent removed under reduced pressure. Flash chromatography(50% EtOAc/hexane) afforded 474 mg of5-phenylsulfanylimidazole-1-sulfonic acid dimethylamide (2) and 290 mgof 5-phenylsulfanyl-1H-imidazole (3) (H). The 478mg of (2) was added to2N HCI and the solution heated at reflux for 2 h. The reaction mixturewas made basic with 2N NaOH and extracted with ethyl acetate. Theorganic layer was washed with water followed by brine. The solution wasdried over sodium sulfate and the solvent removed under reducedpressure. Flash chromatography (EtOAc) afforded (3) as a whitecrystalline solid. A combined total of 360 mg (2.0 mmol) of (3) isrecovered.

[0107]¹H NMR (300 MHz, CD₃OD) 7.91 (s, 1H), 7.37 (s, 1H), 7.19-7.23 (m,2H), 7.07-7.11 (m, 3H).

EXAMPLE I

[0108] Procedure for Preparation of4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)4,5-dihydro-1H-imidazole,methane sulfonic acid salt:

[0109] mmol in anhydrous THF (250 mL) at 20° C. under argon was added3.26 mL (32.90 mmol) borane-dimethylsulfide (BH3-Me₂S) via syringe.After stirring for 16 h MeOH (4 mL) was added and the mixture was warmedto 55° C. until no more gas was evolved. The mixture was concentrated toan oil, taken up in Et₂O and washed successively with 2M phosphoricacid, saturated sodium bicarbonate, water and brine and then dried overMgSO₄ and reconcentrated. The resulting oil was purified by high vacuumKugelrohr at 150° C. to give pure alcohol(1,2,3,4-tetrahydronaphthalen-2-yl)methanol (2) (4.09 g) in 93% yield.To triphenylphosphine (10.179 g, 38.809 mmol) and imidazole (2.64 g,38.809 mmol) in anhydrous benzene (175 mL) was added the iodine (8.60 g,33.865 mmol) in benzene (75 mL) with rapid stirring followed by (2) inbenzene (50 mL). After 3 h the solids were filtered off and the filtratewas reduced in vacuo to a volume of 50 mL to which was added hexane (200mL). The resultant solids were filtered off and the filtrate was washedsuccessively with water and brine, dried over MgSO₄ and concentrated invacuo. The resulting oil was purified by flash chromatography on silicawith hexane to give pure 2-iodomethyl-1,2,3,4-tetrahydronaphthalene (3)(6.239 g) in 90% yield. To (3) (10.02 g, 36.85 mmol) and CuI (1.41 g,7.37 mmol) in anhydrous THF (50 mL) at −78° C. under argon was addedvinylmagnesium bromide (1M in THF, 73.70 mL, 73.70 mmol) slowly at aspeed at which no color developed. This solution was allowed to warm to0° C. and stirred for 6 h. The resulting mixture was recooled to −40° C.and quenched by the careful addition of 2M phosphoric acid (35 mL). Thissolution was diluted with 100 mL water and extracted with hexanes. Theorganic fractions were washed successively with water and brine, driedover MgSO₄ and concentrated in vacuo. The resulting oil was purified byflash chromatography on silica with hexane to give²-allyl-1,2,3,4tetrahydronaphthalene (4) (5.618 g) in 88% yield. (4)(5.615 g, 32.645 mmol) and meta-chloroperbenzoic acid (m-CPBA) (14.08 g,81.613 mmol) were stirred in anhydrous methylene chloride (50 mL) for 16h. The solids were filtered off and potassium flouride THF (5.11 g,88.142 mmol) was added and this mixture was stirred an additional hour.The solids were filtered off and the reaction was concentrated in vacuo.The resulting oil was purified by flash chromatography on silica with 5%ethyl acetate in hexane to give2-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)oxirane (5) (5.41 g) in 88%yield. To (5) (1.626 g, 8.649 mmol) in a solution of acetone (20 mL) andwater (5 mL) was added sodium azide (1.97 g, 30.271 mmol). This solutionwas warmed to 85° C. and stirred for 48 h. The solution was concentratedin vacuo and the residues were taken up in CHCl₃ and washed successivelywith water and brine, dried over MgSO₄ and concentrated in vacuo. Theresulting oil was purified by flash chromatography on silica with 30%ethyl acetate in hexane to give pure1-azido-3-(1,2,3,4-tetrahydronaphthalen-2-yl)propan-2-ol (6) (1.762 g)in 88% yield. A mixture of (6) (1.88 g, 8.140 mmol), triphenylphosphine(2.67 g, 10.173 mmol), phthalimide (1.50 g, 10.173 mmol), diethylazodicarboxylate (DEAD) (1.77 g, 10.173 mmol) were stirred in anhydrousTHF (50 mL) for 4 h. This solution was concentrated in vacuo, taken upin a solution of hexane (25 mL) and ether (25 mL) and stirred for 16 h.The solids were filtered off and the filtrate was concentrated in vacuo.The resulting oil was purified by flash chromatography on silica with20% ethyl acetate in hexane to give2-[1-azidomethyl-2-(1,2,3,4-tetrahydronaphthalen-2-yl)ethyllisoindole-1,3-dione(7) (2.487 g) contaminated with a small amount of impurity which wascarried on without further purification. A mixture of (7) (3.93 g,10.917 mmol) and hydrazine (0.680 mL, 21.833 mmol) were heated inethanol (60 mL) at reflux for 16 h. The solids were filtered off and thefiltrate was concentrated in vacuo. The residues were purified by flashchromatography on silica with 5% MeOH in CH₂Cl₂ to give1-azidomethyl-2-(1,2,3,4-tetrahydronaphthalen-2-yl)ethylamine (8) (2.057g) in 88% yield. A mixture of (8) (2.056 g, 8.940 mmol) and 10%palladium on carbon (0.260 g) were stirred in MeOH (30 mL) under 1atmosphere of hydrogen for 16 h. The solids were filtered off and thefiltrate was concentrated in vacuo. The residues were purified by flashchromatography on silica with 10% ammonia saturated MeOH in CH₂Cl₂ togive 3-(1,2,3,4-tetrahydronaphthalen-2-yl)propane-1,2-dione (9) (1.557g) in 85% yield. A mixture of (9) ,0.590 g, 2.892 mmol) andmethanesulfonic acid (0.980 mL, 14.460 mmol) were heated intriethylorthoformate (10 mL) at 105° C. 3 h. The reaction wasconcentrated in vacuo and the solids were filtered off. Subsequentrecrystalization of these solids from a mixture of MeOH and ether gavepure4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4,5-dihydro-1H-imidazole,methane sulfonic acid salt (I) (0.435 g) in 48% yield.

[0110]¹H NMR (CDCl₃): 1.37 to 1.56 (m, 1H); 1.56 to 1.70 (m, 1H); 1.80to 2.02 (m, 2H); 2.32 to 2.55 (m, 21); 2.72 (s, 3H); 2.75 to 2.95 (m,3H); 3.48 to 3.59 (m, 1H); 3.93 to 4.08 (m, 1H); 4.31 to 4.47(m, 1H);7.00 to 7.20 (m, 4H); 8.46 (s, 1H); 10.04 (s, 1H1); 10.35 (brs, 1H).

EXAMPLE J-1

[0111] Procedure for Preparation of 4(5)-cyclohexylmethyl-1H-imidazole:

[0112] Procedure-

[0113] 2-Tert-butyldimethylsilyl-1-dimethylsulfamoyl imidazole (1) (4.1g, 14.2 mmol) is taken up in 47 mL of anhydrous THF and cooled to −20°C. n-BuLi (8.9 mL, 14.2 mmol) is added dropwise to the solution of (1).The resultant solution is stirred at −20° C. for 45 min.Cyclohexylmethyl iodide (2) (3.14 g, 14 mmol) is then added dropwise tothe reaction mixture. Then reaction is warmed to rt and stirredovernight. The next day the reaction is quenched with saturated ammoniumchloride and diluted with water. The mixture is extracted with ethylacetate (3×100 mL). The organic layers are combined and washed withwater followed by brine. The organic phase is dried over sodium sulfateand the solvent removed under reduced pressure. Flash chromatography(4:1 ethyl acetate/hexane) affords 2.26 g (5.6 mmol) of5-cyclohexylmethyl-2-tert-butyldimethylsilyl-1-dimethylsulfamoylimidazole (3). (3) (2.26 g, 5.6 mmol) is taken up in 56 mL of THF andcooled to 0° C. A 1M solution of TBAF in THF (5.6 mL, 5.6 mmol) is addeddropwise to the solution of (3). The reaction is warmed to rt andstirred overnight. The next day the reaction is quenched with water andthen extracted with ethyl acetate. The organic layer is washed withwater followed by brine. The organic phase is dried over sodium sulfateand the solvent removed under reduced pressure. Flash chromatography(1:1 ethyl acetate/hexane) affords 1.2 g (4.42 mmol) of5-cyclohexylmethyl -1-dimethylsulfamoyl imidazole (4). (4) (1.2 g, 4.42mmol) is taken up in 25 mL of a 1.5N HCl solution and heated at refluxfor 2 h. The reaction is cool to rt and diluted with ethyl acetate. Themixture is brought to pH 13 with 2N NaOH and then extracted withchloroform (4×100 mL). The organic layers are combined and washed withwater followed by brine. The organic phase is dried over sodium sulfateand the solvent removed under reduced pressure. Flash chromatography(9:1 chloroform/methanol) affords 700 mg (4.27 mmol) of4(5)-cyclohexylmethyl-1H-imidazole (5) (J-1).

[0114]¹H NMR (CDCl₃): 0.92 to 1.0 (m, 2H); 1.16 to 1.26 (m, 3H); 1.57 to1.73 (m, 6H); 2.48 (d, J=6.9 Hz, 2H); 6.77 (s, 1H); 7.56 (s, 1H)

EXAMPLE J-2

[0115] (S)-2-iodomethyl-1,2,3,4-tetrahydronaphthalene is substitutedinto the method of Example J-1 to yield(S)4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole.(S)-2-iodomethyl-1,2,3,4-tetrahydronaphthalene was prepared from(S)-1,2,3,4-tetrahydro-2-naphthoic acid. (S)-1,2,3,4tetrahydro-2-naphthoic acid was prepared from the resolution of1,2,3,4-tetrahydro-2-naphthoic acid (J. Med. Chem. 1983, 26, 328-334)

EXAMPLE J-3

[0116] (R)-2-iodomethyl-1,2,3,4-tetrahydronaphthalene is substitutedinto the method of Example J-1 to yield(R)-4(5)-(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole.(R)-2-iodomethyl-1,2,3,4-tetrahydronaphthalene was prepared from(R)-1,2,3,4-tetrahydro-2-naphthoic acid.(R)-1,2,3,4-tetrahydro-2-naphthoic acid was prepared from the resolutionof 1,2,3,4-tetrahydro-2-naphthoic acid J. Med. Chem. 1983, 26, 328-334)

EXAMPLE K-1

[0117] Procedure for Preparation of4(5)-(4,5,6,7-tetrahydrobenzolb]thiophen-2-ylmethyl)-1H-imidazole:

[0118] Procedure-

[0119] 4,5,6,7-tetrahydrobenzofblthiophene (1) (2.1 g, 15 mmol) is takenup in 75 mL of anhydrous THF and cooled to −78° C. n-BuLi (6.0 mL, 15mmol) is added dropwise to the solution of (1). The resultant solutionis stirred at −78° C. for 60 min.1-Dimethylsulfamoyl-2-t-butyldimethylsilyl-5-imidazolecarboxaldehyde (2)(4.8 g, 15 mmol) in 25 mL of THF is added to the reaction. The reactionis warmed to rt and stirred for 2 h before being quenched with water anddiluted with ethyl acetate. The organic layer is washed with waterfollowed by brine. The organic phase is dried over sodium sulfate andthe solvent removed under reduced pressure. Flash chromatography (1:3ethyl acetate/hexane) affords 5.2 g (11 mmol) of 2-(tert-butyldimethylsilyl)-5-[hydroxy-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)methyl]imidazole-1-sulfonic acid dimethylamide (3). (3) (5.2 g, 11.3mmol) is taken up in 57 mL of THF. A 1M solution oftetra-n-butylammonium fluoride (TBAF) in THF (11.3 mL, 11.3 mmol) isadded dropwise to the solution of (3). The reaction is stirred for 1 h15min reaction before being quenched with water and then extracted withethyl acetate. The organic layer is washed with water followed by brine.The organic phase is dried over sodium sulfate and the solvent removedunder reduced pressure. Recrystallization from hexane/ethyl acetateaffords5-[hydroxy-(4,5,6,7-tetrahydrobenzofl)thiophen-2-yl)methyl]imidazole-1-sulfonicacid dimethylamide (4) (2.1 g, 6.2 mmol). An additional 2 g of the crudeproduct is also recovered. (4) (2.0 g, 5.9 mmol) is taken up in 78 mL ofdichloromethane, to the solution is added 7.5 mL (46.9 mmol) oftriethylsilane and 14.4 mL (0.19 mol) of trifluoroacetic acid. Thereaction is stirred at rt overnight and then quenched with water andneutralized with 2N NaOH. The organic layer is washed with waterfollowed by brine. The organic phase is dried over sodium sulfate andthe solvent removed under reduced pressure. Flash chromatography using a1:1 mixture of ethyl acetate and hexane affords 0.75 g (2.3 mmol) of5-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylmethyl)imidazole-1-sulfonicacid dimethylamide (5). (5) (0.42 g, 1.55 mmol) is taken up in 15 mL ofa 1.5N HCl solution and heated at reflux for 2 h and then stirred at rtovernight. The reaction is diluted with ethyl acetate, neutralized with2N NaOH. The organic layer is washed with water followed by brine. Theorganic phase is dried over sodium sulfate and the solvent removed underreduced pressure. The crude product is dissolved in methanol and anexcess of HCl in ether is added. Solvent is removed under reducedpressure to afford 0.6 g (2.3 mmol) of4(5)-(4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylmethyl)-1H-imidazole (6)(K-1).

[0120]¹H NMR (CD₃OD): 8.80 (s, 1H); 7.34 (s, 1H); 6.57 (s, 1H); 4.18 (s,2H); 2.65 to 2.69 (m, 2H); 2.51 to 2.55 (m, 2H); 1.74 to 1.83 (m, 4H)

EXAMPLE K-2

[0121] 2-(Tert-butyl) furan is substituted into the method of ExampleK-1 to yield 4(5)-(5-tert-butylfiuran-2-ylmethyl)-1H-imidazole

EXAMPLE K-3

[0122] 5,6-Dihydro4H-thieno[2,3-b]thiopyran is substituted into themethod of Example K-1 to yield4(5)-(5,6-dihydro-4H-thieno[2,3-b]thiopyran-2- ylmethyl)-1H-imidazole

EXAMPLE L

[0123] Procedure for Preparation of4(5)-(1-furan-2-ylethyl)-1H-imidazole:

[0124] Procedure-

[0125] 2-(Tert-butyldimnethylsilyl)-1-(dirnethylsulfamoyl)imidazole (1)(3.3 g, 11.4 mmol) is taken up in 38 mL of anhydrous THF and cooled to−78° C. n-BuLi (7.2 mL, 11.4 mmol) is added dropwise to the solution of(1). The resultant solution is stirred at -78° C for 30 min. 2-Furfural(2) (0.94 mL, 11.4 mmol) is added to the reaction. The reaction iswarmed to rt and stirred overnight. The next day the reaction isquenched with saturated ammonium chloride and diluted with ethylacetate. The organic layer is washed with water followed by brine. Theorganic phase is dried over sodium sulfate and the solvent removed underreduced pressure. Flash chromatography (4:1 ethyl acetate/hexane)affords 4.4 g (11.4 nmuol) of2-(t-butyldimethylsilyl)-5-(furan-2-ylhydroxy-methyl)imidazole-1-sulfonicacid dimethylamide (3). (3) (4.4 g, 11.4 mmol) is taken up in 110 mL ofTHF and cool to 0° C. A 1M solution of tetra-n-butylammonium fluoride(TBAF) in THF (11.4 mL, 11.4 mmol) is added dropwise to the solution of(3). The reaction is stirred overnight at rt. The next day the reactionis quenched with water and then extracted with ethyl acetate. Theorganic layer is washed with water followed by brine. The organic phaseis dried over sodium sulfate and the solvent removed under reducedpressure. 3.9 g of crude 5-(furan-2-ylhydroxymethyl)imidazole-1-sulfonicacid dimethylamide (4) is recovered. (4) (1.0 g, 3.7 mmol) is taken upin 37 mL of dichloromethane, to the solution is added 1.6 g (18.5 mmol)of manganese dioxide. The reaction is stirred at rt overnight and thenfiltered through celite. The eluent is collected and the solvent removedunder reduced pressure. Flash chromatography using a 1:1 mixture ofethyl acetate and hexane affords 0.69 g (2.6 nmuol) of5-(furan-2-ylcarbonyl)imidazole-1-sulfonic acid dimethylamide (5). (5)(0.69 g, 2.6 mmol) is taken up in 26 mL of THF. The solution is cool to−78° C. 1.7 mL (5.1 mmol) of a 3M solution of methylmagnesium chlorideis added. After stirring at −78° C. for 1.5 h reaction is warmed to rtand stirred for an additional hour. The reaction is quenched with waterand then extracted with ethyl acetate. The organic layer is washed withwater followed by brine. The organic phase is dried over sodium sulfateand the solvent removed under reduced pressure. Crystallization fromether/hexane affords 0.39 g (1.4 mmol) of 5-(1-furan-2-yl-1-hydroxyethyl)imidazole-1-sulfonic acid dimethylamide (6). Anadditional 0.19 g of (6) is recovered. (6) (0.58 g, 2.0 mmol) is takenup in 27 mL of dichloromethane, to the solution is added 2.6 mL (16.3mmol) of triethylsilane and 5.5 mL (71.4 mmol) of trifluoroacetic acid.The reaction is stirred at rt overnight and then quenched with water andneutralized with solid sodium bicarbonate. The organic layer is washedwith water followed by brine. The organic phase is dried over sodiumsulfate and the solvent removed under reduced pressure.

[0126] Flash chromatography using a 2:1 mixture of ethyl acetate andhexane affords 0.53 g (2.0 mmol) of5-(1-furan-2-ylethyl)imidazole-1-sulfonic acid dimethylamide (7). (7)(0.34 g, 1.3 mmol) is taken up in 10 mL of a 1.5N HCl solution andheated at reflux for 30 min and then stirred at rt overnight. Thereaction is diluted with ethyl acetate and then made basic with 2N NaOH.The organic layer is washed with water followed by brine. The organicphase is dried over sodium sulfate and the solvent removed under reducedpressure. Flash chromatography (10:1 chloroform/methanol) affords 0.1 g(0.62 mmol) of 4(5)-(1-furan-2-ylethyl)-1H-imidazole (8) (L).

[0127]¹H NMR (300 MHz, CDCl₃) 7.56 (m, 1H), 7.33-7.34 (m, 1H), 6.81 (m,1H), 6.29-6.31 (m,1H), 6.06-6.07 (m,1H), 4.22 (q, J=7.2 Hz, 1H), 1.63(d, J=7.2 Hz, 3H).

EXAMPLE M

[0128] Procedure for Preparation of4(5)-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)4-methyl-1H-imidazole:

[0129] Procedure-

[0130] 4-Methyl-1-(dimethylsulfamoyl)imidazole (1) (2.0 g, 10.6 mmol) istaken up in 42 mL of anhydrous THF and cooled to −78° C. n-BuLi (6.6 mL,10.6 mmol) is added dropwise to the solution of (1). The resultantsolution is stirred at −78° C. for 30 min.Tert-Butyldimethylsilylchloride (TBSCl) (1.6 g, 10.6 mmol) in 10 mL ofTHF is added to the reaction. The reaction is warned to rt and stirredovernight. The next day the reaction is cooled to −20° C. and 7.3 mL(11.6 mmol) of n-BuLi added. After stirring at −20° C. for 30 min,1,4benzodioxan-6-carboxaldehyde (2) (1.92 g, 11.7 mmol) in 10 mL of THFis added to the reaction mixture. Then reaction is warmed to rt andstirred for 3 h. The reaction is quenched with water and diluted withethyl acetate. The organic layer is washed with water followed by brine.The organic phase is dried over sodium sulfate and the solvent removedunder reduced pressure. Flash chromatography (1:2 ethyl acetate/hexane)affords 3.9 g (8.4 mmol) of 2-(t-butyldimethylsilyl)-5-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydroxyethyl]4-methylimidazole-1-sulfonic aciddimethylamide (3). (3) (1.0 g, 2.14 mmol) is taken up in 21 mL of THF. A1M solution of tetra-n-butylammonium fluoride (TBAF) in THF (2.35 mL,2.35 mmol) is added dropwise to the solution of (3). The reaction isstirred for 30 min at rt. The reaction is quenched with water and thenextracted with ethyl acetate. The organic layer is washed with waterfollowed by brine. The organic phase is dried over sodium sulfate andthe solvent removed under reduced pressure. Flash chromatography usingethyl acetate as eluant affords 0.75 g (2.12 mmol)5-[(2,3-dihydrobenzo[1,4]dioxin-6-yl)hydroxymethyl]4-methylimidazole-1-sulfonicacid dimethylamide (4). (4) (0.75 g, 2.12 mmol) is taken up in 28 mL ofdichloromethane, to the solution is added 2.7 mL (17.0 mmol) oftriethylsilane and 5.2 mL (67.8 mmol) of trifluoroacetic acid. Thereaction is stirred at rt overnight and then quenched with water andneutralized with solid sodium bicarbonate. The organic layer is washedwith water followed by brine. The organic phase is dried over sodiumsulfate and the solvent removed under reduced pressure. Flashchromatography using a 3:1 mixture of ethyl acetate and hexane affords0.63 g (1.87 mmol) of5-(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-4-methylimidazole-1-sulfonicacid dimethylamide (5). (5) (0.63 g, 1.87 mmol) is taken up in 10 mL ofa 1.5N HCl solution and heated at reflux for. The reaction is dilutedwith ethyl acetate, neutralized with solid sodium bicarbonate. Theorganic layer is washed with water followed by brine. The organic phaseis dried over sodium sulfate and the solvent removed under reducedpressure. Crystallization from ether/hexane affords 0.33 g (1.43 mmol)of 4(5)-(2,3-dihydrobenzo[1,4]dioxin-6-ylnethyl)-4-methyl-1H-imidazole(6) (M).

[0131]¹H NMR (300 MHz, acetone-d⁶) 7.37 (s, 1H), 6.66-6.67 (m, 3H), 4.18(s, 4H), 3.73 (s,1H), 2.13 (s, 3H)

EXAMPLE N

[0132] Procedure for Preparation of2-(3H-indazole-4(5)-ylmethyl)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one(N-1), 4(5)-(2,3,4,4a,5,6,7,8-octahydronaphthlen-2-ylmethyl)-1H-indazole(N-2) and 4(5)-(1,2,3,4,5,6,7,8-octahydronaphthalene-2-ylmethyl)-1H-imidazole (N-3):

[0133] Procedure:

[0134] 1-Decalone (10.0 g, 66 mmol) and 4(5)-imidazole carboxaldehyde(6.3 g, 66 mmol) were added to 100 mL of ethanol. To the solution wasadded NaOH (5.2 g, 130 mmol) in 30 mL of water. The reaction was heatedat reflux for 5 days. The reaction was cooled to rt and made basic withaqueous HCl. The solution was extracted with THF/ethyl acetate. Theorganic layers were combined and washed with brine. The organic phasewas dried over magnesium sulfate and the solvent removed under reducedpressure to afford the crude product. The crude product was heated atreflux in 40% H₂SO₄ for 1 day. The reaction was cooled to rt and madebasic with saturated K₂CO₃. The solution was extracted with THF/ ethylacetate. The organic layers were combined and washed with brine. Theorganic phase was dried over magnesium sulfate and the solvent removedunder reduced pressure. Purification by flash chromatography (15:1CH₃Cl/MeOH) afforded N-1 (4.9 g, 32% yield). ¹H NMR: 7.55 (s,1H), 6.77(s, 1H), 3.08-3.14 (m, 2H), 1.52-2.46 (m, 13H).

[0135] The free base of the hydrochloride salt of N-1 (3.0 g, 11 mmol)was generated with NaOH and then added to diethylene glycol (100 mL). Tothe solution was added hydrazine hydrate (3.2 mL, 100 mmol) and thereaction was left to stir overnight at rt. NaOH (3.1 g, 77 mmol) wasadded and the solution heated at reflux for 5 days. The reaction wascooled to rt and diluted with water. The solution was extracted withTHF/ ethyl acetate. The organic layers were combined and washed withbrine. The organic phase was dried over magnesium sulfate and thesolvent removed under reduced pressure. Purification by flashchromatography (8:1 CH₃Cl/MeOH) afforded N-2 (0.64 g, 27% yield). ¹HNMR: 7.58 (s,1H), 6.76 (s, 1H), 5.24 (d, J=4.3 Hz, 1H), 0.91-2.58 (m,16H).

[0136] N-2 (1.0 g, 4.6 mmol) was added to 10 mL of concentrated HCl. Thesolution was stirred at rt for 30 min and then neutralized with K₂CO₃.The solution was extracted with THF/ethyl acetate. The organic layerswere combined and washed with brine. The organic phase was dried overmagnesium sulfate and the solvent removed under reduced pressure.Purification by flash chromatography (15:1 CH₃Cl/MeOH) afforded N-3. ¹HNMR: 7.54 (s,1H), 6.74 (s, 1H), 2.45-2.52 (m, 3H), 1.46-1.97 (m, 14H).

EXAMPLE O

[0137] Procedure for Preparation of 4(5)-octahydropentalen-2-ylmethyl)-1H-imidazole, hydrochloride:

[0138] Procedure-

[0139] A. Following the synthesis of White and Whitesell, Synthesis pp.602-3 (1975), ether (10 mL) was added to a flame-dried flask cooled to0° C. and then kept under an argon atmosphere. Then n-butyl lithium (35mL of 2.5 M solution in hexane, 2.2 equiv.) was added and subsequentlydiisopropyl amine (14 mL, 2.5 equiv.) was added slowly and the mixturewas allowed to stir for 30 min. at 0° C. To this generated solution oflithium diisopropyl amide was added cyclooctene oxide (5.0 g, 1.0equiv.). The mixture was stirred at rt for one day and then heated toreflux under argon atmosphere for 2 days. The reaction was quenched byaddition of NH₄Cl. The solution was extracted with THF/EtOAc. Theorganic extracts were combined, washed with brine, dried over magnesiumsulfate and concentrated in vacuo to afford a yellow brown oil which wasthe 1-hydroxy-octahydropentalene. The compound was used without furtherpurification in the next step.

[0140] B. The alcohol thus obtained (5.0 g, 1 equiv.) was dissolved indichloromethane (200 mL) and to this solution was added pyridiniumchlorochromate (13 g, 1.5 equiv.) and the mixture was stirred at rt forone day. The solution was then filtered through a short column of SiO₂using diethyl ether as eluent. The obtained solution was concentrated invacuo to afford a pale green-yellow oil which was used without furtherpurification in the next step.

[0141] C. The octahydro-pentalen-1-one (5.0 g, 1.0 equiv.) of the abovestep was added to 4(5)-imidazolecarboxaldehyde (3.8 g, 1.0 equiv.) and40% H₂SO₄ (20 ml) and the mixture was maintained at 90° C. for 3 days.The reaction was then quenched by addition of ammonium hydroxide andextracted with tetrahydrofuran/ethyl acetate. The organic extracts werecombined, washed with brine, dried over magnesium sulfate. The resultingaqueous layer was neutralized with HCl/NH₄Cl. The aqueous layer wasre-extracted as above and the combined organic fractions wereconcentrated in vacuo to afford an orange solid.

[0142] D. This orange solid was dissolved in ethanol to which palladiumon carbon (0.5 g) was added. The reaction flask was placed under 40 psiof hydrogen for one day. The reaction solution was filtered thoughcelite with more ethanol used as eluent. The solution was concentratedin vacuo to afford a yellow brown oil. Purification by columnchromatography using 17:1 chloroform/methanol afforded the ketoneproduct in a somewhat impure state.

[0143] E. The ketone functionality was then removed by addition of theproduct of the step above (8.2 g, 1.0 equiv.) to diethylene glycol (80mL)and hydrazine hydrate (13.0 g, 1.0 equiv.). This mixture was stirredovernight and then potassium hydroxide (11.0 g, 5.0 equiv.) was addedand the solution was heated under reflux for one day. The reactionsolution was cooled to rt and washed with water. The solution wasextracted with THF/EtOAc and the combined fractions were washed withbrine, dried over magnesium sulfate and concentrated in vacuo to afforda yellow oil. The monohyrdochloride salt was made by dissolving this oilin anhydrous ethanol saturated with HCl and heating.

EXAMPLE P

[0144] Procedure for the preparation of7-(3H-imidazol-4(5)-ylmethyl)-6,7-dihydro-5H- isoquinolin-8-one (P1) and7-(3H-imidazol-4(5)-ylmethyl)-5, 6, 7, 8-tetrahydroisoquinoline (P-2)

[0145] Procedure:

[0146] A. 3,4-lutidine (21.4 g, 1 equiv.) was dissolved in 200 mL ofwater at 20° C. and potassium permanganate was added in 6.32 g portionstwice daily for 5 days (total 63.2g, 2 equiv.). After 5 days thesolution was stored in the freezer, then thawed and filtered throughcelite. The resulting colorless solution was concentrated at 90° C. on arotary evaporator until a white solid was obtained. This solid wasrecrystallized from 5N HCl to give 9.56 g of white crystals. NMRindicated a mixture of two regioisomers with the desired isomer beingthe major product.

[0147] B. These crystals were heated in anhydrous ethanol saturated withHCl gas under argon and at reflux for 6 h. Then ethanol was removed fromthe solution by rotary evaporation and the residue was taken up in 100mL of water and the pH was adjusted to between 7 and 8 with solid sodiumbicarbonate. The aqueous phase was extracted with diethyl ether (3×) andthe combined organic fractions were washed with brine, dried overmagnesium sulfate and then filtered and concentrated to give a colorlessoil (3.56 g, 10.8% yield).

[0148] C. Diisopropylamine 2.84 g, 1.3 equiv.) was added to n-BuLi(11.21 mL, 1.3 equiv.) in 100 mL of anhydrous THF under argon at −78° C.via syringe to produce lithium diisopropylamide in situ. To thissolution was added the product of B above (3.56 g, 1 equiv.) in 20 mL oftetrahydrofuran, via syringe and the mixture was stirred at −78° C. for20 min. At this point methyl acrylate (4.85 mL 2.5 equiv.) in 20 mL oftetrahydrofuran was added dropwise through a cannula. The solution wasstirred another 2 h before quenching by addition of 40 mL of 10%potassium acetate. The solution was allowed to warm to 20° C. and thenwas concentrated on a rotary evaporator. The aqueous residue wasextracted three times with chloroform. The combined fractions werewashed with brine and dried over magnesium sulfate, filtered andconcentrated to a black solid, which was stored under high vacuum.Chromatography on silica gel with hexanes/ethyl acetate (7/3 → 6/4)afforded 2.41 g (58.2%) of the desired product which was used withoutfurther purification in the next step.

[0149] D. The material from Step C (0.48 g, 1 equiv.) was dissolved in 1mL of 6M HCl and heated at 105° C. for 16 h after which time thesolution was concentrated to a solid by rotary evaporation at 80° C. Theresidue was taken up in 2 mL of water and neutralized with solid sodiumbicarbonate. The neutralized solution was extracted with chloroform (3×)and the combined fractions were washed with brine, dried over magnesiumsulfate and concentrated to a colorless oil. (0.456 g 93.4%).

[0150] E. The isoquinolone (1.91 g, 1 equiv.) obtained in step D abovewas heated with 4(5)-imidazolecarboxaldehyde 1.25 g, 1. equiv.) at 110°C. in 15 mL of 40% sulfuric acid for 30 h. The reaction mixture wasstored for several days at 0° C. under argon. The solution was thendiluted with 20 mL of water and basified to pH 8.9 with NH₄OH. Solidswere collected by filtration and dried with high vacuum. The product wasa yellow solid (2.81 g, 96.1 %) comprising a mixture of both positionalisomers at the exo double bond.

[0151] F. The product of E, above, was dissolved in 150 mL of methanoland to this solution Pd/C (0.412 g, 0.15 wt. equiv.) was added. Themethanolic solution was then saturated with H₂ by repeated evacuationsand H₂back-fill iterations. The solution was stirred under 1 atm.pressure of H₂ for 20 h until TLC revealed that no unsaturated startingmaterial remained. The solution was filtered through celite andconcentrated to an oil. Chromatography on silica using dichloromethaneand methanol (9/1) recovered pure product (1.853 g 6504 %) as a whitefoam. This was taken up in methanol to which fumaric acid (0.4817g, 1.5equiv.) was added with warming to dissolve the solids. The solution wascooled slowly and off-white crystals (0.826 g, 74%) were obtained, whichare represented as the compound P-1. P-2 was obtained by hydrazinereduction in the same manner as described in Step E of Example O above.

EXAMPLE Q

[0152] Procedure for the preparation of(Z)-6-(3H-imidazol-4(5)-ylmethylene)-7,8-dihydro-6H-quinolin-5-one(Q-1),(E)-6-(3H-imidazol-4(5)-ylmethylene)-7,8-dihydro-6H-quinolin-5-one(Q-2), 6-(3H-imidazol-4(5)-ylmethyl)-7,8-dihydro-6H -quinolin-5-one(Q-3), 6-(3H-imidazol-4(5)-ylmethyl)-5,6,7,8-tetrahydroquinoline,dihydrochloride (Q-4) and6-(3H-imidazol-4(5)-ylmethyl)-octahydroquinolin-5-one (Q-5)

[0153] Procedure:

[0154] A. The reactive azido reagent of the first step was generated insitu by addition of iodine monochloride (67.6 g, 1.15 equiv.) in 50 mLof acetonitrile dropwise through a dropping funnel to a stirred slurryof sodium azide (58.84 g, 2.5 equiv.) in 350 mL of anhydrousacetonitrile at −10° C. and under argon. Addition was complete in 30min, the mixture was stirred an additional 30 min and cyclohexenone(34.81 g, 1.0 equiv.) was added via a syringe and then stirred at 20° C.for an additional 20 h. The mixture was then poured into a liter ofwater and extracted with three 200 mL portions of diethyl ether. Thecombined fractions were washed with 5% sodium thiosulfate solution andthen brine. The organic phase was dried over magnesium sulfate, filteredand concentrated in vacuo at 20° C. The residues were taken up in 1 L ofDMSO at 0° C. and a second portion of NaN₃ was added and the mixturestirred while warming to ambient temperature. This mixture was thendiluted with 2.5 L of ice water and extracted ten times withdichloro-methane (10×250 mL). The combined organic fractions wereconcentrated on a rotovap to a volume of ˜1 L and this concentrate wasextracted three times with 250 mL of water, and then brine, and thendried over magnesium sulfate and concentrated to a dark oil (39.5 g) andstored at −40° C. The oil was purified by chromatography on silica using9/1 to 8/2 hexane:ethyl acetate. Two isomers were recovered, the firstwith the azido group a to the ketone function was obtained in 13.22 g,26.6%, yield. The β-isomer was obtained in 15.825 g, 32.0%, yield.

[0155] B. Triphenyl phosphine was dissolved in 20 mL of dichloromethaneand placed under an argon atmosphere at 20 ° C. The β-isomer obtained asdescribed above was added via cannual to the stirred solution andmaintained at 20° C. for 2 h. As the reaction progressed nitrogen wasliberated from the solution, and after 2 h TLC demonstrated there was nostarting material remaining. The solution was concentrated and passedthrough a silica gel column with dichloromethane progressing to 95/5dichloromethane:methanol as eluent. The amidophosphonate intermediatewas obtained in 2.139 g, 65.1%, yield.

[0156] C. The amidophosphonate was dissolved in 100 mL of anhydrouso-xylene and then 10% Pd/C was added with stirring. Freshly distilledacrolein was then added to the mixture via syringe and heated to refluxfor 4 h, after which time the remaining acrolein was added and heatingunder reflux was continued for 44 h under a finger condenser and underargon. At that time TLC indicated some intermediate remained, so 0.5 gaddition Pd/C was added and the mixture again was heated to reflux foranother 8 h. The mixture was cooled to rt, filtered and concentrated ona rotovap to eliminate excess acrolein, until about 100 mL of o-xylenesolution remained. This solution was cooled by addition of ice, and wasextracted three times with 1N HCl. The combined aqueous fractions wereextracted 3×with Et₂O. The aqueous phase was then cooled to 0° C. andthe pH was adjusted to ˜10 using concentrated NaOH. The aqueous was thenextracted 5× with 100 mL portions of chloroform. The combined chloroformfractions were washed with water and then brined and dried overmagnesium sulfate, filtered, and finally concentrated to give 3.51 g ofan oil in 84.4% yield of 7,8-dihydro-6H-quinolin-5-one.

[0157] D. The 4(5)-imidazole carboxaldehyde was condensed with thequinolinone as described in Step E of Example P and was obtained bothQ-1 and Q-2.

[0158] E. The exo double bond was then reduced with palladium on carbonas described in Step F of Example P above to yield two products whichwere separated by chromatography to give Q-3 and A.

[0159] F. The keto group was removed by the same hydrazine reductionprocedure as that described in Step E of Example O above to give Q4.

[0160] G. The fully-reduced quinoline ring product Q-5 was obtained by astandard reduction of A with lithium/ammonia. (Li, 10 equiv., in NH₃ at−78° C. for 10 min. quenched with NH₄OH, gradual warming with NH₃evaporation).

EXAMPLE R-1

[0161] Procedure for the preparation of(E)-6-(3H-imidazol-4(5)-ylmethylene)-7,8-dihydro-6H-quinoxalin-5-one

[0162] Procedure:

[0163] A. A mixture of 5,6,7,8-tetrahydroquinoxaline (23.75 g, 1equiv.), benzaldehyde (19.81 mL, 1.1 equiv.) and acetic anhydride (33.4mL, 2.0 equiv.) was stirred at 150° C. under argon for 15 hr, afterwhich time TLC indicated mostly desired product with some startingmaterials remaining. Starting materials were removed by vacuumdistillation using a Vigreux column at 170° C. The pot residue was thensubjected to Kugelrohr distillation from 170 -220° C. The first fractionwas slightly contaminated with starting materials (4.71 g). A secondfraction was pure (18.93g). After applying high vacuum to the firstfraction it crystallized. Combined fractions yielded 20.11 g, 51%.

[0164] B. The product from A, above, was dissolved in 100 mL of methanoland warmed slightly, then cooled to−35 to −40° C. and ozone was bubbledthrough the solution. After a few minutes the starting material began tocrystallize out of solution and the solution was warmed and another 200mL of methanol was added and then the reaction was resumed. After about30 minutes the solution turned pale blue. Nitrogen was then introducedby bubbling through the solution for 30 minutes, then methyl sulfide(3.5 mL) was injected into the solution, whereafter the solution wasstirred for another 30 min. at −35° C., then allowed to warm to ambienttemperature with stirring. After about 48 hr. at 20° C. the mixture wassteam distilled to remove solvents to provide a residue of 8.4 g of ayellow-brown oil. This residue was taken up in diethyl ether andextracted 3×with 25 mL portions of 1N HCl. The combined aqueousfractions were washed with diethyl ether 3×. The aqueous solution wasgradually basified to a pH of 8 with concentrated NaOH. The free aminewas then extracted from the aqueous phase with chloroform (3×). Thecombined chloroform extracts were washed twice with brine, dried ofMgSO₄ and concentrated to a yellow oil (3.01 g) After keeping under highvacuum for 1 hr., 2.97g remained. This was recrystallized from diethylether to give 2.35 g of a bright yellow solid. Yield 67.5%.

[0165] c. The 7,8-dihydroquinoxalin-5-one and4(5)-imidazolecarboxaldehyde (Aldrich Chemicals) were suspended in 75 mLof anhydrous tetrahydrofuran at 20° C. under argon followed by additionof piperidine followed by acetic acid. The mixture was stirred 16 h at20° C. After 20 h, no traces of the quinoxalone remained as indicated byTLC. The solids were collected by filtration and washed with a smallamount of tetrahydrofuran, followed by chloroform. The solid was driedunder high vacuum to give 6.85 g of R-1. Yield 90.3%.

EXAMPLE R-2 and R-3

[0166] In a similar manner as R-1,5,6,7,8-tetrahydroisoquinoline (5.42g, 1 equiv., Aldrich) was stirred with benzaldehyde (5.182 g, 1.2equiv.) and acetic anhydride (6.309 g, 2.0 g) which was vacuum distilledand used without further purification in the next step. Yield (impure):8.28 g.

[0167] The crude product (7.96 g) from the step above was subjected toozonolysis as described in Step B above. After work-up andchromatography there was obtained 5.18 g of a pale oil. Yield: 97.8%assuming pure starting material.

[0168] The resulting 7,8-dihydro-6H-isoquinolin-5-one (1.692 g, 1equiv.) was condensed with 4(5)-imidazolecarboxaldehyde as described inStep C above to yield 2.23 g of the unsaturated compound analogous toR-1 in the scheme above in 92.8% yield. This product was treated withpalladium on carbon as described in Step F of Example P to reduce theexo double bond to produce 6-(3H-imidazol-4(5)-ylmethyl)-7,8-dihydro-6H-isoquinolin-5-one (R-2) in 52%.

[0169] The ketone above was reduced using hydrazine and converted to thefumarate salt as detailed in Example P, Step F. Yield for the reduction:62%. Yield of fumarate salt after recrystallization: 30.4% of6-(3H-imidazol-4(5)-ylmethyl)-5,6,7,8-tetraydroisoquinoline (R-3).

EXAMPLE S

[0170] Procedure for the preparation4(5)-(4a-methyl-2,3,4,4a,5,6,7,8-octahydro-naphthalen-2-ylmethyl)-l1H-imidazole, but-2-enedioic acid salt:

[0171] Procedure -

[0172] Methyl triphenylphosphonium bromide (2.75 g, 7.70 mmol) wassuspended in 50 mL of diethyl ether. At −10° C., nBuLi (3.08 mL, 7.70mmol, 2.5M soln in hexanes) was added. This mixture was stirred for 35 mbefore cooling to -70° C. A solution of(R)-(+)-4,4a,5,6,7,8-hexahydro-4a-methyl-2(3H)-naphthalenone (1) (1.0 g,6.09 mmol) in 15 mL of ether was added via syringe. This mixture waswarmed to 0° C. over 30 m and the stirred at rt for another 30 m. Thesolution was washed with brine (2×20 mL) dried over MgSO₄, filtered andthe solvent was removed. Chromatography on SiO₂ with hexanes gave 0.82 g(83%) of the diene 2 as a clear colorless oil.

[0173] This hydroboration procedure follows that by Brown, H. C. et. al.J Am. Chem. Soc. 1969, 91, 2144. To a solution of the diene 2 (750 mg,4.63 mmol) in 20 mL of THF was added 9-BBN (11.8 mL , 5.9 mmol, of a 0.5M soln. in THF) at 0° C. This was warmed to rt after 30 m and allowed toreact at rt for 1 h. Dry MeOH (3.75 mL, 15.0 mmol as a 4.0 M soln inTHF) was added to a stirred solution of LiA1H₄ (5.04 mL, 5.04 mmol, 1.0M in ether) to form LiAIH(OMe)₃. The borane was added to this alkoxyaluminum hydride via syringe. After 10 m at rt, carbon monoxide wasbubbled through the solution for 20 m. Phosphate buffer (25 mL, pH 7.0was added followed by H₂O₂ (10 mL, 30% soln) and this was stirred for 30m. After a typical extraction process the oil was purified bychromatography on SiO₂ with 5 to 10% EtOAc:Hx to yield the colorlessaldehyde 3 as the major product 455 mg, (51%).

[0174] This preparation followed the protocol by Horne, D. A.;Yakushijin, K.; Büichi, G. Heterocycles, 1994, 39, 139. A solution ofthe above aldehyde 3 (450 mg, 2.34 mmol) in EtOH (8 mL) was treated withtosylmethyl isocyanide (TosMIC) (430 mg, 220 mmol) and NaCN (˜15 mg,cat) at rt for 20 m. The solvent was removed in vacuo and the residuedissolved in MeOH saturated with NH₃ (10 mL). The solution was heated ina resealable tube at 110° C. for 6-12 h. The material was concentratedand purified by chromatography on SiO₂ with 5% MeOH (sat. w/ NH₃):CH₂Cl₂ to give the imidazole as a thick glass 193 mg (36%).

[0175] The imidazole was purified further by stirring in THF or MeOHwith an equimolar amount of fumaric acid at rt for 10 m. The solvent wasremoved and the salt recrystallized by dilution in THF and titurationwith ether:hexanes for a 70-80% recovery of pure fumarate 4 (S).

[0176]¹H NMR (500 MHz, DMSO-d₆ w/TMS): δ7.73 (s, 1 H), 6.83 (s, 1 H),6.60 (s, 2 H), 5.12 (s, 1 H), 2.45-2.44 (m, 2 H), 2.30 (brs, 1 H), 2.12(brs, 1 H), 1.91-1.88 (m, 1 H), 1.73-1.71 (m, 1 H), 1.56-1.46 (m, 5 H),1.30-1.09 (series of m, 4 H), 1.01 (s, 3 H)

[0177]¹³C (125 MHz, DMSO-d₆ w/TMS): δ167.0, 143.5, 134.8, 134.5, 128.7,123.7, 118.2, 42.3, 36.7, 35.0, 32.8, 32.5 (2C), 28.4, 25.9, 24.4, 22.3.

EXAMPLE T-1

[0178] Procedure for the preparation4(5)-(3-methyl-cyclohex-2-enylmethyl)-1H-imidazole, but-2-enedioic acidsalt:

[0179] Procedure-

[0180] A solution of 3-methyl-2-cyclohexen-1-one (1) (5 g, 45.4 mmol) in25 mL of ether was added dropwise via an addition funnel to a solutionof LiA1H₄ (45 mL, 1M in THF) in ether (100 mL) at −10° C. After 1 h themixture was carefully quenched with NH₄Cl (10 mL) and treated with 10%HCl (7 mL). The organic layer was extracted with ether (3 ×70 mL), driedover MgSO₄, filtered and concentrated. The residue was purified bychromatography by elution with 20% EtOAc:Hx to give 2, a clear colorlessalcohol, 4.46 g (88%).

[0181] A solution of alcohol 2 (1.68 g, 15 mmol) in ethyl vinyl ether(38 mL) was treated with Hg(OAc)₂ (3.2 g, 10 mmol) and NaOAc (410 mg, 5mmol) at 35° C. for 4 h. The mixture was poured onto 5% KOH solution (15mL), diluted with ether and extracted with hexanes. The organic layerwas dried over Na₂SO₄, filtered and concentrated. The crude residue wasused in the next step without further purification.

[0182] According to the procedure by Greico, P. A.; et al, J Am Chem.Soc. 1991, 113, 5488, a 3M solution of LiClO₄ (16 g, 150 mmol) in 50 mLof ether was treated with the crude vinyl ether 3 at rt for 30 m. Theentire mixture was poured onto sodium bicarbonate solution (150 mL).After extraction of the aldehyde 4 with ether, the organic layer wasdried over MgSO₄, filtered, and concentrated under reduced pressure. Thecrude residue was purified by chromatography on SiO₂ with EtOAc:Hx orsubmitted to the Buichi protocol as described above for the formation ofthe imidazole-fumarate 5 (8% from 6 to free base of 5).

[0183]¹H NMR (500 MHz, d⁶-DMSO w/TMS) : δ7.71 (s, 1 H), 6.82 (s, 1 H),6.61 (s, 2 H), 5.27 (s, 1 H), 2.46-2.32 (series of m, 3 H), 1.85 (brs, 2H), 1.60 (s, 3 H), 1.35-0.86 (series of m, 4 H)

[0184]¹³C (125 MHz, DMSO-d₆ w/TMS): δ167.3, 134.9,134.5, 125.5, 118.1,35.5, 32.6, 30.1, 28.5,24.0, 21.4.

EXAMPLE T-2

[0185] 4(5)-(3,5,5-trimethyl-cyclohex-2-enylmethyl)-1H-imidazole,but-2-enedioic acid salt is prepared by substituting isophorone in themethod of T-1

EXAMPLE T-3

[0186] 4(5)-(3-methyl cyclopent-2-enylmethyl)-1H-imidazole,but-2-enedioic acid salt is prepared by substituting3-methyl-2cylopenten-1-one in the method of T-1

EXAMPLE U-1

[0187] Procedure for the preparation4(5)-cyclohex-2-enylmethyl-1H-imidazole, but-2- enedioic acid salt:

[0188] Procedure -

[0189] A solution of cyclohexenone (1) (2.88 g, 30 mmol) in hexanes at−78° C. was treated with DIBAL (30 mL, 1.0 M in cyclohexane). After 25m, MeOH (7 mL) was added and the mixture was warmed to rt. A saturatedsolution of Rochelle's salt was added followed by dilution with ether(100 mL). The organic layer was separated, dried over MgSO₄, filteredand concentrated under vacuum. The product was purified bychromatography on SiO₂ with 20% EtOAc:Hx to give a clear colorlessalcohol 2, 2.0 g (68%).

[0190] A solution of the above alcohol 23 (2.0 g, 20.4 mmol) in triethylorthoacetate (30 mL) and propionic acid (˜0.025 mL, cat) was heated toremove ethanol. After the ethanol was removed heating was continued at145° C. for 1 h. The triethyl orthoacetate was removed by simpledistillation. After the residue cooled to rt the product was purified bychromatography on SiO₂ with 5% ether:Hx to give ester 3 as a clearcolorless oil 1.08 g (˜31%).

[0191] A solution of the above ethyl ester 3 (1.0 g, 5.9 mmol) wasdissolved in hexanes (50 mL) and cooled to −78° C. A solution of DIBAL(5.8 mL 1.0 M in cyclohexane) was added dropwise. After 15 m, diethylether (50 nL) was added and the mixture was stirred with Rochelle's saltsolution (25 mL) for 10 m. The organic layer was separated, dried andfiltered. Chromatography on SiO₂ with 7% Et₂O:Hx delivered the aldehydeas a clear colorless oil, 0.52 g (74%). The aldehyde 4 was subjected tothe Büchi protocol as described above. The fumarate salt of theimidazole 5 (U-1) was obtained in three steps (25% overall).

[0192]¹H NMR (500 MHz, DMSO-d6 w/TMS) : δ7.67 (s, 1 H), 6.80 (s, 1 H),6.60 (s, 2 H), 5.66-5.54 (m, 2 H), 2.52-2.42 (m, 2 H), 2.34 (brs, 1 H),1.93 (s, 2 H), 1.66 (brs, 2 H), 1.46-1.43 (m, 1 H), 1.22-1.16 (m, 1 H)

[0193]¹³C (125 MHz, DMSO-d₆w/TMS): δ166.3, 134.3, 134.2, 131.2, 126.9,118.1, 96.5, 35.0, 32.5, 28.4, 24.8, 20.7.

EXAMPLE U-2

[0194] 4(5)-(4-methyl-cyclohex-2-enylmethyl)-1H-imidazole,but-2-enedioic acid salt is prepared by substituting6-methyl-2-cyclohexen-1-one in the method of U-1

EXAMPLE V

[0195] Procedure for the preparation of2-(1H-Imidazole-4(5)-ylmethyl)-cyclohexanone, but-2-enedioic acid salt:

[0196] Procedure -

[0197] To the 4(5)-imidazolecarboxaldehyde (2.52 g, 26.23 mmol)suspended in cyclohexanone (25.74 g, 262..25 mmol) under argon added thepiperadine (0.56 g, 6.56 mmol) and acetic acid (0.52 g, 8.65 mmol).After heating at reflux for 16 h. the cyclohexanone was removed bykugelrohr. Chromatography on SiO₂ with 5-10% MeOH (saturated with NH₃):CH₂Cl₂ gave 4.07 g (88%) of unsaturated imidazole 1 as an oil.

[0198] The unsaturated imidazole 1 (1.02 g, 5.81 mmol) in MeOH (40 ml)containing palladium (10 wt. % on activated carbon) (0.15 g) washydrogenated at 1 atmosphere pressure of H₂. After 16 h the palladiumwas filtered off and the filtrate was concentrated at reduced pressure.The imidazole was recrystallized by stirring in MeOH with an equimolaramount of fulmaric acid until all solids had disappeared followed by theaddition of a small amount of diethyl ether and cold storage. The titlecompound 2 (V) 0.80 g (48%) was recovered as white crystals.

[0199]¹H NMR (300 MHz, CDCl₃ w/TMS) : δ9.5-6.5 (vbs, 3H), 7.71(s, 1H),6.80 (s, 1H), 6.60 (s, 2H), 2.91(dd, J=14.8 Hz, J=5.4 Hz, 1H), 2.75-2.60(m, 1H), 2.42-2.28 (m, 2H), 2.27-2.17 (m, 1H), 2.02-1.89 (m, 2H),1.78-1.68 (m, 1H), 1.68-1.45 (m, 2H), 1.32-1.17 (m, 1H)

[0200]¹³C NMR (75 MHz, DMSO-d₆ w/TMS): δ211.6, 166.6, 134.4, 134.2,133.8, 117.4, 49.7, 41.4, 33.1, 27.5, 25.8, 24.3.

EXAMPLE W-1

[0201] Procedure for the preparation of4(5)-(3,4-Dimethyl-cyclohex-3-enylmethyl)-1H- imidazole, but-2-enedioicacid salt:

[0202] Procedure -

[0203] 2,3-Dimethyl-1,3-butadiene (10.16 g, 123.72 mmol), ethyl acrylate(11.06 g, 110.47 mmol) and hydroquinone (0.12 g, 1.11 mmol) were heatedwith stirring at 165° .C in a sealed tube for 16 h and then at 205° C.for an additional 4 h. Kugelrohr distillation of the resulting residueat 150° C. and 0.5 torr gave 14.11 g (70%) of cyclohexene ester 1 as anoil in the 20° C. bulb. To a solution of the ester 1 (13.62 g, 72.32mmol) in anhydrous THF (200 ml) at −78° C. under argon added the LiA1H₄(54.30 ml, 1 M in diethyl ether). This mixture was stirred for 1 h at20° C. and then quenched at 0° C. by the careful, consecutive additionof H₂O(2.06 ml), NaOH (2.06 ml of a 15% aqueous solution), and anadditional portion of H₂O(6.18 ml). The solids were filtered off and thefiltrate was concentrated under reduced pressure. Kugelrohr distillationof the resulting residue at 150-180° C. and 0.5 torr gave 9.98 g (98%)of the alcohol 2 as a colorless volatile oil in the 0° C. bulb. To asolution of triphenyl phosphine (27.13 g, 103.45 mmol), and imidazole(7.04 g, 103.45 mmol) in anhydrous benzene (450 ml) under argon wasadded the I₂(22.75 g, 89.61 mmol) in benzene (170 ml) over a period of10 minutes with rapid mechanical stirring. After an additional 10minutes the alcohol 2 (9.23 g, 65.89 mmol) in benzene (100 ml) was addedto this rapidly stirring mixture over a period of 5 minutes. After 2 hthe reaction was diluted with hexanes (800 ml) and the solids werefiltered off. The organics were washed with 3 portions of H₂O (800 ml),dried (MgSO₄), filtered and concentrated under reduced pressure. Theresidual solids were filtered off and the resulting oil was purified bykugelrohr distillation at 200° C. and 0.5 torr to give 11.99 g (73%) ofthe iodide 3 as a pale oil in the 0° C. bulb. To a solution of thepreviously described 1- N-(dimethylsulfamoyl)-2-tert-butyldimethylsilylimidazole (4.34 g, 15.00 mmol) in anhydrous THF (50 ml) at −78° C. underargon was added n-butyllithium (5.76 ml, 2.5 M in hexanes). This mixturewas stirred for 10 minutes at −10° C. and then cooled to −20° C. beforeadding the iodide 3 (3.00 g, 12.00 mmol) in THF (25 ml) dropwise viacannula. The resulting solution was stirred for 16 h at 20° C., thenquenched with saturated aqueous NaHCO₃ and concentrated under reducedpressure. The residues were taken up in diethyl ether and washedconsecutively with H₂O and brine, dried (MgSO4) and concentrated.Subsequent purification by chromatography on SiO₂ with 5-10%EtOAc:hexanes gave 0.89 g (15%) of the imidazole 4 as a pale oil. To asolution of imidazole 4 (0.89 g, 2.17 mmol) in anhydrous THF (25 ml)under argon was added tetrabutylammonium fluoride (2.38 ml, 1 M in THF)and the resultant solution was stirred for 1 h at 20° C. The mixture wasconcentrated under reduced pressure and the residues were taken up indiethyl ether and washed consecutively with saturated aqueous NaHCO₃ andbrine, dried (MgSO₄) and concentrated. The residues were purified bychromatography on SiO₂ with 50% EtOAc:hexanes to give 0.56 g (87%) ofthe imidazole 5 as a pale oil. To a solution of 5 (0.53 g, 1.77 mmol) inMeOH (5 ml) was added aqueous KOH (15 ml of a SM solution) and themixture was heated at reflux for 32 h. The mixture was concentratedunder reduced pressure, diluted with H₂O (5 ml) and extractedexhaustively with CHCl₃. The combined organic fractions were washedconsecutively with H₂O and brine, dried (MgSO₄) and concentrated underreduced pressure. The imidazole was recrystallized by stirring in MeOHwith an equimolar amount of fumaric acid until all solids haddisappeared followed by the addition of a small amount of diethyl ether.The title compound 6 (W-1) 0.27 g (57%) was recovered as pale crystals.

[0204]¹H NMR (300 MHz, DMSO-d₆ w/TMS) : δ10.3-8.8 (vbs, 3 H), 7.88 (s,1H), 6.89 (s, 1H), 6.59 (s, 2H), 2.48 (d, J=6.7 Hz, 2 H), 2.00-1.70 (m,4 H), 1.70-1.57 (m, 2 H), 1.56 (s, 3 H), 1.54 (s, 3 H), 1.21-1.04 (m,1H) )

[0205]¹³C NMR (75 MHz, DMSO-d₆ w/TMS): δ166.7, 134.4, 134.1, 133.4,124.8, 124.3, 117.9, 37.6, 34.1, 32.2, 31.1, 28.7, 19.0, 18.7.

EXAMPLE W-2

[0206] 4(5)-Cyclohex-3-enylmethyl-H-imidazole, but-2-enedioic acid saltis prepared by substituting 3-cyclohexene-1-methanol in the method ofW-1

EXAMPLE X-1

[0207] Procedure for the preparation of4(5)-(4-Methyl-cyclohex-3-enylmethyl)-1H-imidazole, but-2-enedioic acidsalt:

[0208] Procedure - To a slurry of NaH (60% in oil) (6.92 g, 288.28 mmol)in anhydrous THF (1500 ml) at 0° C. under argon with vigorous mechanicalstirring added the trimethyl phosphonoacetate (52.50 g, 288.28 mmol)dropwise. Stirred this mixture an additional 30 minutes before addingthe 1,4-cyclohexanedione mono-ethylene ketal (40.93 g, 262.07 mmol) inTHF (170 ml) dropwise. The mixture was stirred an additional 18 h at 20°C. and then concentrated under reduced pressure. This residue was takenup in diethyl ether (1000 ml) and washed consecutively with H₂O andbrine, dried (MgSO₄), filtered and concentrated to give 60.08 g,(98%) ofthe unsaturated ester 1 which was carried on without furtherpurification. To a solution of unsaturated ester 1 in EtOAc (500 ml)added the palladium (10 wt. % on activated carbon) (2.13 g). This slurrywas saturated with H₂ by repeated evacuations and H₂ backfills and thenstirred for 16 h under one atmosphere pressure of H₂. Celite (5 g) wasadded to the reaction, the palladium was filtered off and the filtratewas concentrated under reduced pressure to give 59.45 g (98%) of thesaturated ester 2 which was carried on without further purification. Toa solution of LiA1H₄ (200.00 ml, 1 M in diethyl ether) at −78° C. underargon was added the unsaturated ester 2 in anhydrous THF (400 ml) in aslow stream with vigorous mechanical stirring. Upon warming to 20° C.additional THF (600 ml) was added and the reaction was stirred 1 h. Themixture was cooled to 0° C. and quenched by the careful, consecutiveaddition of H₂O (7.60 ml), NaOH (7.60 ml of a 15% aqueous solution), andan additional portion of H₂O (22.80 ml). The solids were filtered offand the filtrate was concentrated under reduced pressure. Subsequentpurification by chromatography on SiO₂ with 20-50% EtOAc:hexanes gave50.93 g (98%) of the alcohol 3 as a pale oil. To a solution of oxalylchloride (20.65 ml, 41.29 mmol) in anhydrous CH₂Cl₂ (100 ml) at −78° C.under argon was added dropwise a solution of DMSO (6.72 g, 86.02 mmol)in CH₂Cl₂ (25 ml). After mechanical stirring for 15 minutes a solutionof the alcohol 3 (6.40 g, 34.41 mmol) in CH₂Cl₂ (80 ml) was addeddropwise and the mixture was stirred an additional 15 min at −78° C.before adding triethylamine (27.85 g, 275.30 mmol). The reaction wasstirred 2 h at 20° C. and then quenched with saturated aqueous NaHCO₃.This mixture was extracted CH₂Cl₂ and the combined organic fractionswere washed consecutively with H₂O and brine, dried (MgSO₄) andconcentrated under reduced pressure. The resulting solids were purifiedby chromatography on SiO₂ with 20-30% EtOAc:hexanes to give 5.08 g,(79%) of the aldehyde 4 as a white solid. A solution of aldehyde 4 (5.08g, 27.59 mmol) in EtOH (40 ml) was treated with tosylmethyl isocyanide(TosMIC) (5.15 g, 26.27 mmol) and NaCN (0.13 g, 2.68 mmol) at 20° C. for3 h and then refrigerated. After 2 h refrigeration the solids werefiltered off, dissolved in anhydrous MeOH saturated with NH₃ (30 ml) andheated in a sealed tube at 100° C. for 3.5 h. The reaction was thenconcentrated under reduced pressure and the residues were taken up inCHCl₃, washed consecutively with saturated aqueous NAHCO₃ and brine,dried (MgSO₄) and concentrated to a red oil. This residue was furtherpurified by chromatography on SiO₂ with 5-10% MeOH (saturated with NH₃):CH₂Cl₂ to give 1.87 g (31%) of the imidazole 5 as a pink oil. A solutionof 5 (0.55 g, 2.48 mmol) in acetone (20 ml) containing HCl (5 N, 0.5 ml)was stirred for 5 h. The reaction was concentrated under reducedpressure, the residues were taken up in H₂O neutralized to pH 7 withsaturated aqueous NaHCO₃ and extracted exhaustively with CHCl₃/isopropylalcohol (3:1). The combined organic portions were washed consecutivelywith H₂O and brine, dried (MgSO₄) and concentrated. Chromatography onSiO₂ with 5-10% MeOH (saturated with NH₃): CH₂Cl₂ gave 0.43 g (97%) ofthe desired ketone 6. A solution of 6 (0.20 g, 1.11 mmol) in anhydrousDMF (4 ml) under argon was treated with triethylamine (0.14 g, 1.33mmol) and dimethylsulfamoyl chloride (0.19 g, 1.33 mmol) under argon andstirred 16 h. The solids were filtered off and the filtrate wasconcentrated at via kugelrohr at 100° C. and 0.5 torr. The residues weretaken up in CHCl₃ and washed consecutively with H₂O and brine, dried(MgSO₄) and concentrated. Chromatography on SiO₂ with 1-5% MeOH:CH₂Cl₂gave 0.22 g (69%) of the desired protected imidazole 7 as a mixture ofregioisomers which were carried on without separation. A solution of 7(0.18 g, 0.62 mmol) in anhydrous THF (10 ml) under argon was treatedwith methylmagnesium chloride (0.32 ml, 3.0 M in THF) and the resultingmixture was stirred 16 h. The reaction was quenched with a small amountof MeOH, concentrated under reduced pressure and the residues were takenup in H₂O. The mixture was acidified by the dropwise addition of 1 N HCluntil the solution was homogenious and then the pH was adjusted to 7with saturated aqueous NaHCO₃. The organic materials were extracted intoCHCl₃ and the combined organic portions were washed consecutively withH₂0 and brine, dried (MgSO₄) and concentrated. Chromatography on Si0₂with 5% MeOH:CH₂Cl₂ gave 0.18 g (95%) of the alcohol 8 as a mixture ofregioisomers which were carried on without separation. A solution of 8(0.14 g, 0.46 mmol) in anhydrous benzene (3 ml) at 0° C. under argon wastreated with (methoxycarbonylsulfamoyl) triethylammonium hydroxide,inner salt (Burgess reagent) (0.12 g, 0.51 mmol) and stirred 1 h at 20°C. The reaction was concentrated under reduced pressure and subsequentpurification by chromatography on SiO₂ with 5% MeOH:CH₂Cl₂ gave 0.12 g(92%) of the alkenes 9 and 10 as a mixture of isomers which were carriedon without separation. The mixture of isomers 9 and 10 (0.12 g, 0.42mmol) were refluxed in a solution composed of MeOH (2 ml) and KOH (2 mlof a 5 N solution) for 30 h. The reaction was concentrated under reducedpressure and the residues were taken up in H₂O and extractedexhaustively with CHCl₃. The combined organic portions were washedconsecutively with H₂O and brine, dried (MgSO₄) and concentrated.Chromatography on SiO₂ with 5-10% MeOH (saturated with NH₃): CH₂Cl₂ gave0.05 g (67%) of alkenes 11 and 12 as a mixture of isomers which werecarried on without separation. The mixture of alkenes 11 and 12 (0.045g, 0.26 mmol) and p-toluenesulfonic acid hydrate (0.063 g, 0.32 mmol)were heated at reflux in 1,2-dichloroethane (2 ml) under argon for 20 h.The reaction was concentrated under reduced pressure and the residueswere purified by chromatography on SiO₂ with 10% MeOH (saturated withNH₃): CH₂Cl₂ to give the free base of imidazole 13 (X-1) as one isomer.The imidazole was recrystallized by stirring in MeOH or THF with anequimolar amount of fumaric acid until all solids had disappearedfollowed by the addition of a small amount of diethyl ether and coldstorage. The title compound 13 (X-1) 0.040 g (54%) was recovered aswhite crystals.

[0209]¹H NMR (300 MHz, DMSO w/TMS) δ7.65 (s, 1 H), 6.78 (s, 1 H), 6.60(s, 2 H), 5.31 (s, 1 H), 2.44 (d, J=6.7 Hz, 2 H), 2.02-1.82 (m, 3 H),1.82-1.60 (m, 3 H), 1.59 (s, 3 H), 1.26-1.11 (m, 1 H)

[0210]¹³C NMR (75MHz, DMSO-d₆ w/TMS): δ175.0, 165.2, 134.3, 134.1,133.2, 120.3, 118.3, 33.2, 32.4, 31.2, 29.3, 28.3, 23.4.

EXAMPLE X-2

[0211] 4(5)-(4-Ethyl-cyclohex-3-enylmethyl)-1H-imidazole, but-2-enedioicacid salt is prepared by substituting ethyl magnesium chloride in themethod of X-1

EXAMPLE X-3

[0212] 4(5)-(4-Pentyl-cyclohex-3-enylmethyl)-1H-imidazole,but-2-enedioic acid salt is prepared by substituting pentyl magnesiumchloride in the method of X-1

EXAMPLE Y

[0213] A method for measuring α-agonist selectivity comprises the RSAT(Receptor Selection and Amplification Technology) assay as reported inMessier et al. (1995) “High throughput assays of cloned adrenergic,muscarinic, neurokinin and neurotrophin receptors in living mammaliancells”, Phannacol. Toxicol. 76:308-11 and adapted for use with alpha₂receptors. The assay measures a receptor-mediated loss of contactinhibition that results in selective proliferation ofreceptor-containing cells in a mixed population of confluent cells. Theincrease in cell number is assessed with an appropriate transfectedmarker gene such as b-galactosidase, the activity of which can be easilymeasured in a 96-well format. Receptors that activate the G protein,G_(q), elicit this response. Alpha₂ receptors, which normally couple toG_(i), activate the RSAT response when coexpressed with a hybrid G_(q)protein that has a G_(i) receptor recognition domain, called G_(q)/i5².See Conklin et al. (1993) “Substitution of three amino acids switchesreceptor specificity of G_(q)a to thatof G_(i)a.” Nature 363:274-6.

[0214] NIH-3T3 cells are plated at a density of 2×106⁶ cells in 15 cmdishes and maintained in Dulbecco's modified Eagle's medium supplementedwith 10% calf serum. One day later, cells are cotransfected by calciumphosphate precipitation with mammalian expression plasmids encodingp-SV-b-galactosidase (5-10 mg), receptor (1-2 mg) and G protein (1-2mg). 40 mg salmon sperm DNA may also be included in the transfectionmixture.

[0215] Fresh media is added on the following day and 1-2 days later,cells are harvested and frozen in 50 assay aliquots. Cells are thawedand 100 ml added to 100 ml aliquots of various concentrations of drugsin triplicate in 96-well dishes. Incubations continue 72-96 hr at 37°.After washing with phosphate-buffered saline, b-galactosidase enzymeactivity is determined by adding 200 ml of the chromogenic substrate(consisting of 3.5 mM o-nitrophenyl-b-D-galactopyranoside and 0.5%nonidet P-40 in phosphate buffered saline), incubating overnight at 30°and measuring optical density at 420 nm. The absorbence is a measure ofenzyme activity, which depends on cell number and reflects areceptor-mediated cell proliferation. The EC₅₀ and maximal effect ofeach drug at each alpha₂ receptor is determined. The efficacy orintrinsic activity is calculated as a ratio of the maximal effect of thedrug to the maximal effect of a standard full agonist for each receptorsubtype. Brimonidine, also called UK14,304-18, is used as the standardagonist for the alpha_(2A) and alpha_(2C) receptors. Oxymetazoline isthe standard agonist used for the alpha_(2B) receptor.

[0216] Table 1, below, provides the intrinsic activity values atsubtypes of the α2-adrenoreceptor as determined in the RSAT assay forthe compounds of above Examples B through X and certain adrenergiccompounds not having selective agonist activity at the α2B or α2B/α2Csubtype(s). At the α2A subtype, the compounds of the Examples areinactive or exhibit low efficacy (≦0.4). They have greater efficacy atthe α2B and the α2C-subtypes than the α2A-subtype. Therefore, unlikeophthalmic α2-adrenoreceptor compounds such as clonidine andbrimonidine, the compounds of Examples B through X can selectivelyactivate α2-adrenoreceptor subtypes other than the α2A-subtype. TABLE 1Intrinsic Activity Relative to Brimonidine/Oxymetazoline BrimonidineOxymetazoline Brimonidine Example Structure/Compound Alpha 2A Alpha 2BAlpha 2C oxymetazoline 0.63 1.0 0.58 clonidine 0.78 0.75 0.55brimonidine 1.0 0.93 1.0 4(5)-(3-methyl-thiophen-2- 0.43 1.4 0.5ylmethyl)-1 H-imidazole D-3

0 0.4 0 D-1

0 0.47 0 F

0.3 0.9 0.2 G

0.1 0.87 0.33 J1

0.1 0.83 0 E-1

0.33 0.83 0.35 M

0.2 0.97 0.27 C-2

0.23 1.3 0.5 C-1

0 0.83 0 C-9

0.06 0.88 0.43 C-3

0.1 0.88 0.43 C-8

0.3 0.9 0.4 H

0.2 0.93 0.15 C-5

0 1.1 0.4 B-3b

0 0.7 0 J-2

0 0.8 0 J-3

0.1 1 0.15 L

0.23 0.9 0.57 C-6

0.2 0.67 0.1 C-4

0.05 0.82 0.5 D-2

0.25 0.75 0 C-10

0.05 0.48 0.1 C-7

0.08 0.73 0.2 B-3a

0.1 0.8 0.07 I

0 0.5 0.2 B-2a

0 0.63 0.15 B-2b

0 0.77 0 B-2d

0 0.6 0 B-2c

0 0.65 0 B-9a

0.08 0.46 0 B-4a

0 0.75 0.1 B-4b

0.3 0.7 0.6 B-11b

0 0.3 0 B-6

0 0.35 0 B-5b

0 0.5 0.2 B-5a

0 0.5 0.37 B-7a

0 0.3 0 B-11a

0.4 0.9 0 B-7b

0 0.3 0 B-1

0.15 0.45 0.3 B-1a

0.15 0.6 0 B-9b

0 0.68 0.15 B-7c

0 0.9 0 B-10

0 0.3 0 B-8b

0 0.6 0.2 B-8a

0 0.4 0 K-1

0 0.53 0 C-12

0.2 1.3 0.3 C-13

0 0.5 0 K-3

0 0.37 0 K-2

0 0.7 0 C-11

0.2 0.5 0 C-14

0.27 0.7 0.3 N-1

0.24 0.75 0.26 Q-3

0.1 0.9 0.23 Q-2

0.1 0.87 0.13 Q-1

0 0.75 0.2 N-2

0 0.5 0.05 Q-4

0.1 0.8 0.1 O

0 0.67 0.1 B-9c

0 0.3 0 R-3

0 0.6 0.4 R-2

0 0.6 0.4 R-1

0.3 0.8 0.4 P1

0 0.4 0 P-2

0 0.4 0 N-3

0 0.75 0 A-5

0 1.0 0 S

0 .6 0 T-1

0.25 0.8 0.35 T-2

0 0.7 0 T-3

0 1.08 0.36 U-1

0.17 0.6 0.43 U-2

0.2 0.6 0.3 V

0 0.4 0.5 W-1

0.07 0.55 0.07 W-2

0 0.6 0.7 X-1

0.15 0.8 0.11 X-2

0 0.56 0 X-3

0.19 0.87 0

EXAMPLE Z

[0217] IOP-Lowering and Sedative Side Effects

[0218] Measurements of IOP were made in fully conscious femalecynomolgus monkeys weighing 34 kg with sustained elevated IOP that wasproduced in the right eye by argon laser photocoagulation of thetrabecular meshwork. Animals were usable for experiments ˜2 monthsfollowing surgery. During the experiments, monkeys sat in speciallydesigned chairs (Primate Products, San Prancisco), and were fed orangejuice and fruit as needed. A 30R model Digilab pneumatonometer (Alcon,Tex.) was used to measure IOP.

[0219] Twenty five μl of an anesthetic (proparacaine) was topicallyapplied to each monkey before IOP measurements to minimize oculardiscomfort due to tonometry. Two baseline measurements were made priorto instillation of the drugs, followed by periodic measurements up to 6hours post-instillation. The test compounds were administeredunilaterally as a single 50 μl eye drop; the contralateral eyes receivedan equal volume of saline.

[0220] Many of the α2B or α2B/2C selective compounds of the exampleswere tested in the monkeys. Surprisingly, as Table 2 shows, thesestructurally diverse compounds all lowered IOP in the treated eye.

[0221] At the same time, sedation was measured and assessed according tothe following score: 0=alert, typical vocalization, movement, etc.;1=calm, less movement; 2=slightly sedated, some vocalization, responsiveto stimulation; 3=sedated, no vocalization, some response tostimulation; 4=asleep.

[0222] The compounds of the present invention also did not causesedation. This contrasts with the action of clonidine and brimonidine,which caused sedation.

[0223] Table 2. The effects of α2-adrenoceptor agonists on IOP andsedation in conscious cynomolgus monkeys following ocular administrationin eyes made unilaterally hypertensive by argon laser photocoagulation.Measurements were made periodically up to 6 hours. Sedation was assessedsubjectively during the IOP experiments using the following scoring:0=alert, typical vocalization, movement, etc.; 1=calm, less movement;2=slightly sedated, some vocalization, responsive to stimulation;3=sedated, no vocalization, some response to stimulation; 4=asleep.Number of animals per group=(6-9). TABLE 2 Maximum % Decrease FromPretreatment Levels Compounds Dose (%) Hypertensive Eye Sedation (0-4)Saline —  7 ± 2 0-1 Clonidine 0.1 25 ± 4 1 0.3 41 ± 5 2 Brimonidine 0.125 ± 3 1 0.3 40 ± 4 2 J-1 1 26 ± 5 0 3 33 ± 3 0 E-1 0.3 25 ± 4 0 1 27 ±3 0 C-1 1 25 ± 4 0 3 29 ± 4 0 D-1 1 25.6 ± 3.9 0 M 1 22.5 ± 5.4 0 C-2 129.6 ± 5.5 0 C-9 0.3 13.7 ± 4.5 0 1 25.1 ± 4.9 0 C-3 0.3 20.6 ± 4.8 0 125.0 ± 6.4 0 C-8 1 31.2 ± 3.3 0 B-3b 0.1 25.9 ± 3.5 0 0.3 31.2 ± 4.3 0C-4 0.3 17.7 ± 4.0 0 1 29.3 ± 4.9 0 C-7 1 32.3 ± 5.7 0 J-2 0.03 12.4 ±3.7 0 0.3 27.3 ± 3.1 0 J-3 0.03 16.4 ± 4.7 0 0.3 26.5 ± 3.8 0 B-2d 0.122.0 ± 4.6 0 0.3 17.0 ± 4.2 0 1 18.1 ± 5.2 0 B-9a 0.03 17.6 ± 1.7 0 0.126.7 ± 6.1 0 0.3 24.8 ± 3.3 0 1 26.8 ± 5.4 0 B-6 0.3 13.8 ± 2.4 0 1 22.1± 6.3 0 B-9b 0.1 18.7 ± 5.5 0 0.3 26.9 ± 6.1 0

EXAMPLE AA

[0224] Measurement of Cardiovascular Side Effects

[0225] Cardiovascular measurements were made in a different group ofmonkeys using a BP 100S automated sphygmomanometer (Nippon Colin,Japan). Intravenous (IV) administration of certain of the compounds ofthe present invention at doses ten to thirty times higher than the dosesfor clonidine and brimonidine did not reduce heart rate or lower bloodpressure. Interestingly, the compound4(5)-3-methylthiophen-2-ylmethyl)1H-imidazole, which has intrinsicactivity of 0.43 at the α2A-subtype, exhibited a weak effect on heartrate. Clonidine and brimronidine had even greater effects on heart rate.See Table 3 below.

[0226] Table 3. The effects Of α₂-adrenoceptor agonists oncardiovascular variables in conscious cynomolgus monkeys following i.v.administration.

[0227] Measurements were made periodically up to 6 hours. Number ofanimals per group=(6-10). TABLE 3 Maximum % Decrease From PretreatmentLevels Dose Mean Arterial Blood Compounds (μg/kg) Pressure Heart RateSaline — 7 ± 4 8 ± 3 Clonidine 17 29 ± 7  32 ± 4  50 35 ± 5  50 ± 5 Brimonidine 17 36 ± 3  52 ± 3  50 37 ± 5  54 ± 3  J-1 17   7 ± 5.3 13 ±4  50 4 ± 2 6 ± 2 167 7 ± 5 3 ± 3 500 13 ± 3  7 ± 4 E-1 17 7 ± 4 11 ± 4 50 7 ± 2 14 ± 5  167 9 ± 4 11 ± 5  C-1 50 12.8 ± 12   12 ± 4  500 +5 ±8* +11 ± 9*  M 500 0.8 ± 2.3 5.5 ± 1.9 C-2 500 6.6 ± 1.7 6.5 ± 2.9 C-93.0 5.0 ± 2.3 9.4 ± 3.0 17 1.0 ± 4.1 +9.4 ± 1.8* 50 0.1 ± 3.8  16 ± 3.2500 6.0 ± 2.2 5.9 ± 3.3 C-3 500 2.3 ± 2.7 10.6 ± 3.4  C-8 500 5.5 ± 2.716.6 ± 1.9  C-5 500 3.9 ± 2.8 7.1 ± 3.9 B-3b 50 2.4 ± 4.3 10.0 ± 2.8 C-4 500 5.3 ± 2.9 10.9 ± 3.6  C-7 500 3.0 ± 3.9 6.1 ± 3.7 J-2 500 +0.6 ±3.1* 6.4 ± 3.3 J-3 500 +1.0 ± 2.1* +10.6 ± 6.0*  B-2b 500 5.7 ± 1.4 6.4± 3.6 B-2d 500 +8.9 ± 3.4* +15.5 ± 3.4*  B-9a 500 +10.8 ± 3.2*  +23.8 ±4.4*  B-9b 500 2.8 ± 1.8 +20.2 ± 3.4*  4(5)-(3- 50 9 ± 3 23 ± 4 methylthiophen- 167 8 ± 6 32 ± 8  2-ylmethyl)- 1H-imidazole

EXAMPLE BB

[0228] The studies in the above Examples Z and AA demonstrate that atherapeutic effect of alpha₂ agonists can be separated from sedative andcardiovascular side effects. This separation is accomplished withcompounds that share the property of being preferentially active at thealpha2B and alpha2B/alpha2C subtypes relative to the alpha2A subtype.

[0229] The prior art alpha2 adrenergic agonists, which activate allthree alpha2 receptors, cause sedation, hypotension and bradycardia,preventing or severely limiting their use for treating diseases anddisorders that are known to be ameliorated by them. Such diseases anddisorders include muscle spasticity including hyperactive micturition,diarrhea, diuresis, withdrawal yndromes, pain including neuropathicpain, neurodegenerative diseases including optic neuropathy, spinalischemia and stroke, memory and cognition deficits, attention deficitdisorder, psychoses including manic disorders, anxiety, depression,hypertension, congestive heart failure, cardiac ischemia and nasalcongestion. See, for example, Hieble et al., “Therapeutic applicationsof agents interacting with alpha-adrenoceptors, in Alpha-adrenoceptors:molecular biology, biochemistry and pharmacology”. Prog. Basic Clin.Pharmacol. (Basel, Karger) 8, pp. 180-220(1991). For example, clonidinehas been shown to be clinically effective in providing pain relief forpostoperative, cancer-associated and neurogenic pain. But, as stated inMaze and Tranquilli, Maze MB and Tranquilli, W. “Alpha-2 adrenoceptoragonists: defining the role in clinical anesthesia”. Anesthesiology74,581-605 (1991), the “full clinical promise” of this and other alpha2agonists requires the development of compounds that do not causesedation, hypotension and bradycardia.

[0230] The above-listed diseases and disorders are treatable byactivation of α2B or α2B/2C receptor subtype(s). Therefore, the alpha2compounds described above that have been shown above not to elicitsedation and cardiovascular effects, are useful and advantageous in thetreatment of these conditions.

[0231] Amelioration of neuronal degeneration in glaucomatous neuropathyis another example of the novel utility of the compounds of theinvention. Recent studies have demonstrated that clonidine and otheralpha2 agonists are neuroprotective of retinal cells in several ratmodels of neuronal degeneration. These models include light-inducedphotoreceptor degeneration in albino rat, as described in Wen et al,“Alpha2-adrenergic agonists induce basic fibroblast growth factorexpression in photoreceptors in vivo and ameliorate light damage.” J.Neurosci. 16, 5986-5992 and calibrated rat optic nerve injury resultingin secondary loss of retinal ganglion cells, as described in Yoles etal, “Injury-induced secondary degeneration of rat optic nerve can beattenuated by alpha2-adrenoceptor agonists AGN 191103 and brimonidine”.Invest. Ophthalmol. Vis. Sci. 37, 540,S114. However, unlike thecompounds of the present invention, the doses used in these studies ˜0.1to >1 mg/kg by intraperitoneal or intramuscular injection—also causesedation and cardiovascular effects. Induction of the expression ofbasic fibroblast growth factor (bFGF) is considered a sensitiveindicator of alpha2 receptor activation in the retina (Wen et al above)and measurement of bFGF induction following topical administration ofalpha2 agonists to rat eyes indicates that approximately a 1% dose isnecessary to induce a 2-3 fold increase in bFGF levels that correspondwith alpha2 agonist mediated neuroprotection (See Wen et al, above, andLai et al, “Neuroprotective effect of ocular hypotensive agentbrimonidine”, in Proceedings of XIth Congress of the European Society ofOphthalmology (Bologna, Monduzzi Editore), 439-444.) These topical dosesof current alpha2 agonists such as clonidine are known to result insystemic side effects such as sedation and hypotension that wouldprevent their use as ocular neuroprotective agents. Additionallycommonly assigned and co-pending application, 08/496,292 filed on June28 1995, discloses and claims the use of certain non-selectiveα2-adrenergic agents in treating neural injury, the contents of whichare hereby incorporated by reference in their entirety.

[0232] The compounds of the present invention do not cause sedation andcardiovascular effects following topical administration of doses of atleast 3% in monkeys. Thus, neuroprotective concentrations of thesecompounds can be reached in humans without causing side effects. Infact, as reported below, the compound of Example B-9(b) has been shownto be neuroprotective in the calibrated rat optic nerve injury model ofYoles et al, above. See Table 4, below. TABLE 4 Retinal Ganglion CellNumbers at 2 Weeks Post-Injury (cells/microscopic field) Control ExampleB-9(b) (vehicle i.p.) (0.5 mg/kg i.p.) 33 ± 8  73 ± 12 n = 8 n = 5

[0233] This level of neuroprotection is comparable to the effect seen inprevious studies with the standard alpha 2-adrenoceptor agonist,brimonidine, and the neuroprotective agent, MK801.

EXAMPLE CC

[0234] Alleviation of pain including neuropathic pain is another exampleof a disorder in which the compounds of the invention are useful andadvantageous since pain is alleviated without undesirable side effects.Clonidine, an agonist that activates all three alpha2 receptors, hasbeen used clinically for treating chronic pain, but its utility for thisindication is limited because it causes sedation and cardiovascular sideeffects. Compounds of the present invention were compared to clonidineand brimonidine in a rodent model of neuropathic pain that is known tobe predictive of clinical activity. (See, for example, Kim, S. andChung, J. “An experimental model for peripheral neuropathy produced bysegmental spinal nerve ligation in the rat.” Pain 50 pp. 355-363(1992).) Following ligation of two spinal nerves, the animals develop asensitivity to normally non-painful stimuli such as touch. The abilityof alpha2 compounds to reverse this sensitivity, called allodynia, wastested 30 minutes after dosing by either intrathecal or intraperitonealadministration. The sedative activity of each compound was also measuredusing an activity chamber. The compounds of the invention, exemplifiedby N-1, are able to alleviate the allodynia without causing sedation,even at very high doses. This is in contrast to clonidine andbrimonidine, which cause sedation at doses only slightly higher thantheir anti-allodynic doses. See tables 5 and 6, below. TABLE 5 Theanti-allodynic and sedative effects of alpha2-adrenoceptor agonists inrats 30 minutes following intrathecal administration (N = 6). Reversalof Tactile Compound Dose (μg) Allodynia (%) Sedation (%) Clonidine 0.120* ND 1 96* 15  10 ND 60* N-1 3 13  ND 30 64* 0 300 ND 0

[0235] TABLE 6 The anti-allodynic and sedative effects ofalpha2-adrenoceptor agonists in rats 30 minutes followingintraperitoneal administration (N = 6). Dose Reversal of TactileCompound (mg/kg) Allodynia (%) Sedation (%) Brimondine 3 0 ND 30 37* 24 300 ND 67* N-1 3 3 ND 30 41* ND 10,000 ND 0

[0236] The results of these Examples demonstrate that the common sideeffects of α2-adrenoceptor drugs are mediated by the α2A-subtype andthat their ocular antihypertensive and other therapeutic actions can bemediated by a subtype ther than the α2A-subtype. Thus, α2-adrenoceptorcompounds of unrelated structural classes, that have in common lowfunctional activity at the α2A-subtype, lower IOP and elicit othertherapeutic actions without dose-limiting side effects.

[0237] While in particular embodiments of the invention have beendescribed, it will be understood, of course, that the invention is notlimited thereto since many obvious modifications can be made, and it isintended to include within this invention any such modification as willfall within the claims.

[0238] Having now described the invention, we claim:

What is claimed is:
 1. A compound having selective agonist activity atthe α2B or α2B/α2C adrenergic receptor subtype(s) as compared to the 2Aadrenergic receptor subtype represented by the formula

wherein the dotted lines represent optional double bonds; R is H orlower alkyl; X is S or C(H)R¹, wherein R¹ is H or lower alkyl or R¹ isabsent when X is S or when the bond between X and the ring representedby

is a double bond; Y is O, N, S, (CR¹x)y, wherein y is an integer of from1 to 3, —CH=CH—or —Y¹CH₂—, wherein Y¹ is O, N or S; x is an integer of 1or 2, wherein x is 1 when R², R³ or R⁴ is bound to an unsaturated carbonatom and x is 2 when R², R³ or R⁴ is bonded to a saturated carbon atom;R² is H, lower alkyl, halogen, hydroxy, lower alkoxy, lower alkenyl,acyl or lower alkynyl or, when attached to a saturated carbon atom, R₂may be oxo; R₃ and R₄ are, each, H, lower alkyl, halogen, lower alkenyl,acyl or lower alkynyl, or, when attached to a saturated carbon atom, R₂may be oxo; R₃ and R₄ are, each, H, lower alkyl, halogen, lower alkenyl,acyl, lower alkynyl, aryl, heteroaryl, or substituted aryl orheteroaryl, wherein said substituent is halogen, lower alkyl, loweralkoxy, lower alkenyl, acyl, lower alkynyl, nitro, cyano,trifluoromethyl, hydroxy, or phenyl or, together, are —(C(R²)x)z—;—Y¹(C(R²)x)z′-; —Y¹(C(R²)x)y Y¹—; —(C(R²)x)—Y¹—(C(R²)x)—;—(C(R²)x)—Y¹—(C(R²)x)—(C(R²)x)—and—Y¹—(C(R²)x)—Y¹—(C(R²)x)—wherein z isan integer of from 3 to 5, z′ is an integer of from 2 to 4 and x and yare as defined above, and further either end of each of these divalentmoieties may attach at either R³ or R⁴ to form the condensed ringstructure

and the ring thus formed may be totally unsaturated, partiallyunsaturated, or totally saturated provided that a ring carbon has nomore than 4 valences, nitrogen no more than three and O and S have nomore than two, and including enantiomers and pharmaceutically acceptablesalts thereof.
 2. A compound according to claim 1 wherein said compoundis represented by the formula


3. A compound according to claim 2 wherein X is C(H)R¹.
 4. A compound ofclaim 3 wherein R¹ is H.
 5. A compound of claim 4 wherein R₂ is H and

represents a furanyl radical.
 6. A compound of claim 5 wherein R³ and R⁴together are (CH)₄.
 7. A compound of claim 4 wherein R² is H and

represents a thienyl radical.
 8. A compound of claim 7 wherein R³ andR⁴, together, represent (CH₂)₄.
 9. A compound of claim 7 wherein R³ isphenyl and R⁴ is H.
 10. A compound of claim 7 wherein R³ and R⁴,together, represent (CH₂)₃S.
 11. A compound of claim 7 wherein R³ andR⁴, together, represent (CH)₄.
 12. A compound of claim 4 wherein

represents a cyclohexyl radical.
 13. A compound of claim 12 wherein R²is H. and R³ and R⁴, together, represent (CH)₂S.
 14. A compound of claim12 wherein R² is H, and R³ and R⁴, together, represent (CH₂)₄.
 15. Acompound of claim 12 wherein R² is dimethyl, and R³ and R⁴, together,represent (CH)₄.
 16. A compound of claim 12 wherein Y is —CH₂CH(CH₃)—,R² is hydrogen or oxo, and R³ and R⁴, together, represent (CH)₄.
 17. Acompound of claim 12 wherein R² is oxo or hydrogen, and R³ and R⁴,together, represent S(CH)₂ or S(CH₂)₂.
 18. A compound of claim 12wherein Y is —CH2C(CH)₂—, R² is hydrogen or oxo, and R³ and R⁴,together, represent (CH)₄.
 19. A compound of claim 4 wherein

represents a cyclopentyl radical.
 20. A compound of claim 19 wherein R²is hydrogen, and R³ and R⁴, together, represent (CH₂)₃.
 21. A compoundof claim 4 wherein

represents a phenyl radical.
 22. A compound of claim 1 wherein saidcompound has the formula

wherein Y is S or O.
 23. A compound of claim 1 wherein said compound hasthe formula


24. A compound of claim 23 wherein R³ and R⁴, together, represent (CH)₄.25. A compound of claim 24 wherein Y¹ is O.
 26. A compound of claim 25wherein R² is oxo.
 27. A compound of claim 26 wherein X is CH.
 28. Acompound of claim 26 wherein X is CH₂.
 29. A compound of claim 24wherein one of R² is hydroxy and the other is H.
 30. A compound of claim25 wherein R² is H.
 31. A compound of claim 24 wherein Y¹ is S.
 32. Acompound of claim 31 wherein X is CH₂.
 33. A compound of claim 32wherein R² is oxo.
 34. A compound of claim 32 wherein R² is H.
 35. Acompound of claim 31 wherein X is CH and R² is oxo.
 36. A compound ofclaim 3 wherein Y is (CH₂)₃.
 37. A compound of claim 36 wherein X is CHand R² is oxo.
 38. A compound of claim 36 wherein X is CH₂ and R² is H.39. A compound of claim 2 wherein X is S and

is phenyl.
 40. A compound of claim 3 wherein R¹ is methyl and

is furanyl.
 41. A compound of claim 4 wherein Y is CH₂(CR¹ ₂ )₂ whereinR¹ is hydrogen or methyl.
 42. A compound of claim 41 wherein R² is H.43. A compound of claim 41 wherein R² is oxo.
 44. A compound of claim 3wherein R is CH₃,

represents a phenyl radical and R3 and R4, together represent O(CR₂)₂O.45. A compound of claim 2 wherein X is CH,

represents a cyclopentyl radical and R₂ is oxo.
 46. A compoundrepresented by the formula


47. A compound according to claim 1 represented by the formula

wherein Y is (R¹x)2, R³ +R⁴ is (C(R²)x)4 and X attaches at one of thetwo positions of the ring indicated by the wavy line with the remainingposition being occupied by hydrogen, provided that two double bonds maynot occupy the same ring atom.
 48. A compound according to claim 47wherein said compound is represented by the formula

wherein (R²)_(x) is hydrogen or oxo.
 49. A compound of claim 47 whereinthe structure is


50. A compound of claim 50 wherein the structure is


51. A compound of claim 2 wherein R is hydrogen, R3 and R4 are—(C(R²)_(x))—N—(C(R²)_(x)—(C(R) ²)_(x))—, and X is CHR¹ as representedby the formula

the CHR¹ group attaches at one of the two positions of the ringindicated by the wavy line with the remaining position being occupied byhydrogen, and provided that two double bonds may not occupy the samering atom.
 52. A compound of claim 51 wherein said compound has theformula

and (R²)_(x) is hydrogen or oxo.
 53. A compound of claim 51 wherein saidcompound has the formula

and (R²), is hydrogen or oxo.
 54. A compound of claim 1 wherein R3 andR4 are chosen from the group consisting of —Y¹—(C(R²)x)—(C(R²)x)—Y¹ and—Y¹(C(R²)x)—(C(R²)x) —(C(R²)x)—, and Y¹ is N or O or S as represented bythe formula

wherein X and X′ are selected from the group consisting of N, O and Cand at least one of X and X′ are N.
 55. A compound according to claim 54wherein said compound is represented by the formula

wherein (R²)x is hydrogen or oxo.
 56. A compounds according to claim 54wherein said compound is represented by the formula

wherein (R₂)x is hydrogen or oxo.
 57. A compound having selectiveagonist activity at the α2B or α2B/2C adrenergic receptor subtype(s) ascompared to the α2A adrenergic receptor subtype represented by the

formula and pharmaceutically acceptable salts thereof.
 58. A process foradministering to a host mammnal, including a human being, apharmaceutical composition containing an effective dose of an activecompound to treat or prevent glaucoma without sedating or cardiovascularside effects, wherein said compound has adrenergic activity and is aselective agonist of the α2B adrenoceptor subtype or α2B/(α2Cadrenoceptor subtype(s) in preference over the α2A adrenoceptor subtype.59. A process of claim 58 wherein the active compound has an efficacyrelative to a standard full agonist that is at least approximately 0.3greater at the α2B or α2C adrenoreceptor subtypes than at the α2Aadrenoreceptor subtype and its efficacy at the α2A adrenoreceptorsubtype is ≦0.4.
 60. A process of claim 58 wherein the active compoundis at least ten times more potent at the α2B or α2C adrenoceptor subtypethan at the α2A adrenoceptor receptor.
 61. A process of claim 60 whereinapproximately 0.001% to 5% by weight of the active compound isadministered topically to the host mammal in daily or twice daily doses.62. A process of claim 61wherein approximately 0.01%to 3% byweight ofthe active compound is administered topically to the host mammnal indaily or twice daily doses.
 63. A process of claimr 58 wherein saidcompound has no activity at the α2A adrenoreceptor subtype.
 64. Aprocess of claim 58 wherein said compound has no activity at the α2A andα2C adrenoreceptor subtypes. 65 . A process for administering to a hostmammal, including a human being, a pharmaceutical composition containingan effective dose of an active compound to treat elevated intraocularpressure without sedating or cardiovascular side effects, wherein thecompound has adrenergic activity and is a selective agonist of the α2Bor α2B/ α2C adrenoceptor subtype(s) in preference over the α2Aadrenoceptor receptor subtype.
 66. A process of claim 65 wherein theactive compound has an efficacy relative to a standard full agonist thatis at least approximately 0.3 greater at the α2B or 2C adrenoceptorsubtypes than at the α2A adrenoceptor subtype, and its efficacy at theα2A adrenoceptor subtype is ≦0.4.
 67. A process of claim 66 whereinapproximately 0.001% to 5% by weight of the active compound isadministered topically to the host mammal in daily or twice daily doses.68. A process of claim 67 wherein approximately 0.01% to 3.0% by weightof the active compound is administered topically to the host mammal indaily or twice daily doses.
 69. A process of claimn 65 wherein saidcompound has no activity at the α2A adrenoreceptor subtypes.
 70. Aprocess of claim 65 wherein said compound has no activity at the α2A andα2C adrenoreceptor subtypes.
 71. A method of treating a mammal to lowerintraocular pressure without having cardiovascular and sedative sideeffects by selectively agonizing the α2B adrenoceptor subtype or α2B/α2Cadrenoceptor subtype(s) in preference to the α2A adrenoceptor subtype.72. A method of selectively agonizing the 60 2B adrenoceptor subtype orα2B/α2C adrenoceptor subtypes without agonizing the α2A adrenoceptorsubtype comprising administering a therapeutically effective amount of aselective α2B or α2B/α2C receptor subtype agonist(s) respectively. 73.An alpha adrenergic agonist that selectively activates the α2B orα2B/α2C receptor subtype(s) in preference to the α2A receptor subtype.74. A process according to claims 58, 65 or 71 wherein the activecompound is selected from the group consisting of compounds having theformula

wherein the dotted lines represent optional double bonds; R is H orlower alkyl; X is S or C(H)R¹, wherein R¹ is H or lower alkyl or R¹ isabsent when X is S or when the bond between X and the ring representedby

is a double bond; Y is O, N, S, (CR¹x)y, wherein y is an integer of from1 to 3, —CH=CH—or —Y¹CH₂—, wherein Y¹ is O, N or S; x is an integer of 1or 2, wherein x is 1 when R², R³ or R⁴ is bound to an unsaturated carbonatom and x is 2 when R², R³ or R⁴ is bonded to a saturated carbon atom;R² is H, lower alkyl, halogen, hydroxy or lower alkoxy, or, whenattached to a saturated carbon atom, R₂ may be oxo; R₃ and R₄ are, each,H, lower alkyl, hydroxy, lower alkoxy, or phenyl or, together, are—(C(R²)x)z—; —Y¹(C(R²)x)z′—; —Y¹(C(R²)x)y Y¹—; —(C(R²)x)—Y¹—(C(R²)x)—;—(C(R²)x)—Y¹—(C(R²)x)—(C(R²)x)—and—Y¹—(C(R²)x)—Y¹—(C(R²)x)—wherein z isan integer of from 3 to 5, z′ is an integer of from 2 to 4 and x and yare as defined above, and further either end of each of these divalentmoieties may attach at either R3 or R4 to form the condensed ringstructure

and the ring thus formed may be totally unsaturated, partiallyunsaturated, or totally saturated provided that a ring carbon has nomore than 4 valences, nitrogen no more than three and O and S have nomore than two; or

wherein W is a bicyclic radical selected from the group consisting of

wherein R^(5,) R⁶, R⁷ and R⁸ are selected from the group consisting of Hand lower alkyl provided that at least one of R⁵ and R⁶ or R⁶ and R⁷ areOC(R⁹)C(R⁹)N(R) to form a condensed ring with

wherein R⁹ is H, lower alkyl or oxo and

wherein R¹⁰ is H, lower alkyl, phenyl or lower alkyl substituted phenyl,and Z is O or NH.
 75. A process for administering to a host mammal,including a human being, a pharmaceutical composition containing aneffective dose of an active compound, having adrenergic activity, totreat or prevent glaucoma wherein the active compound has the biologicalproperty that the compound is a selective agonist of α2B or α2B/α2Creceptor subtype(s) in preference over the α2A receptor subtype, saidselectivity being measured in an assay using cells that naturallyexpress the individual α2 subtypes or have had one of the subtypesintroduced, the receptors being human or from a species that has beenshown to have a similar pharmacology, and in which assay the efficacyrelative to a standard compound of the active compound at the α2B or α2Creceptor subtype is measured to be at least 0.3 greater than theefficacy relative to the standard compound of the active compound at theα2A receptor subtype and its efficacy at the α2A receptor subtype is≦0.4, and/or the active compound is at least approximately 10 times morepotent at the α2B or α2C receptor subtypes than at the α2A receptorsubtype.
 76. A process of claim 75 wherein approximately 0.001% to 5% byweight of the active compound is administered topically to the hostmammal per day.
 77. A process for administering to a host mammal,including a human being, a pharmaceutical composition containing aneffective dose of an active compound to treat or prevent musclespasticity including hyperactive micturition, diarrhea, diuresis,withdrawal syndromes, pain including neuropathic pain, neurodegenerativediseases including optic neuropathy, spinal ischemia and stroke, memoryand cognition deficits, attention deficit disorder, psychoses includingmanic disorders, anxiety, depression, hypertension, congestive heartfailure, cardiac ischemia and nasal congestion without sedating orcardiovascular side effects, wherein said compound has adrenergicactivity and is a selective agonist of the α2B or α2B /α2C adrenoceptorreceptor subtype(s) in preference over the α2A adrenoceptor receptorsubtype.
 78. A process for administering to a host mammal, including ahuman being, a pharmaceutical composition containing an effective doseof an active compound, having adrenergic activity, to treat musclespasticity including hyperactive micturition, diarrhea, diuresis,withdrawal syndromes, pain including neuropathic pain, neurodegenerativediseases including optic neuropathy, spinal ischemia and stroke, memoryand cognition deficits, attention deficit disorder, psychoses includingmanic disorders, anxiety, depression, hypertension, congestive heartfailure, cardiac ischemia and nasal congestion without sedating orcardiovascular side effects wherein the active compound has thebiological property that the compound is a selective agonist of α2B orα2B/α2C receptor subtype(s) in preference over the α2A receptor subtype,said selectivity being measured in an assay using cells that naturallyexpress the individual α2 subtypes or have had one of the subtypesintroduced, the receptors being human or from a species that has beenshown to have a similar pharmacology, and in which assay the efficacyrelative to a standard compound of the active compound at the α2B or theα2C receptor subtype is measured to be at least 0.3 greater than theefficacy relative to the standard compound of the active compound at theα2A receptor subtype and its efficacy at the α2A receptor is ≦0.4,and/or the active compound is at least approximately 10 times morepotent at the α2B or α2C receptor subtypes than at the α2A receptorsubtype.
 79. A process for administering to a host mammal, including ahuman being, a pharmaceutical composition containing an effective doseof an active compound, having adrenergic activity, to treat musclespasticity including hyperactive micturition, diarrhea, diuresis,withdrawal syndromes, pain including neuropathic pain, neurodegenerativediseases including optic neuropathy, spinal ischemia and stroke, memoryand cognition deficits, attention deficit disorder, psychoses includingmanic disorders, anxiety, depression, hypertension, congestive heartfailure, cardiac ischemia and nasal congestion without sedating orcardiovascular side effects wherein the active compound has thebiological property that the compound is a selective agonist of α2B orα2B/α2C receptor subtype(s) in preference over the α2A receptor subtype,said selectivity being measured in an RSAT assay in which activation ofthe α2A and α2C receptor subtype by the test compound is compared tobrimnonidine and the α2B receptor subtype is compared to oxymetazolineand wherein the respective a2A, a2B and a2C receptor subtypes areexpressed in NIH-3T3 cells, and in which assay the efficacy relative tobrimonidine of the active compound at the α2C receptor subtype or theefficacy relative to oxymetazoline of the active compound at the α2Breceptor subtype is measured to be at least 0.3 greater than theefficacy relative to brimonidine of the active compound at the α2Areceptor subtype, and its efficacy at the a2A receptor subtype is <0.4and/or the active compound is at least approximately 10 times morepotent at the α2B or α2C receptor subtypes than at the α2A receptorsubtype.
 80. A process of claim 60 wherein the active compound is atleast one hundred times more potent at the α2B or α2C adrenoceptorsubtype than at the α2A adrenoceptor subtype.
 81. The compound of claim4 wherein

represents a cyclopentenyl or a cyclohexenyl radical.
 82. The compoundof claim 81 wherein

represents a cyclohexenyl radical.
 83. The compound of claim 82 wherein

represents

and R² is hydrogen and methyl.
 84. The compound of claim 83 wherein R³is hydrogen or methyl and R⁴ is hydrogen or methyl or one of R³ ismethyl and the other R³ and R⁴ together represent (CH₂)₄.
 85. Thecompound of claim 82 wherein

and R² is hydrogen.
 86. The compound of claim 85 wherein R³ is hydrogenor methyl and R⁴ is hydrogen, methyl, ethyl or n-pentyl.
 87. Thecompound of claim 81 wherein

represents a cyclopentenyl radical.